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| DDG2P v8.1 | FRYL |
Achchuthan Shanmugasundram changed review comment from: PMID:38479391 (2024) reported 14 unrelated individuals with heterozygous FRYL variants (5 missense, 8 frameshift/stop-gain, 1 canonical splice) presenting with developmental delay/intellectual disability, dysmorphic features, and variable congenital anomalies across multiple systems. DD/ID was the only universal feature (14/14); all other phenotypes were variable and nonspecific, and 8/14 individuals harboured additional P/LP variants (in SF3B4, DHCR7, SLC6A19, SDHA) or VUSs in other genes that could partially confound phenotype attribution. Thirteen of 14 variants were confirmed de novo; the remaining variant (p.Ser2397Ile) was not confirmed de novo (duo testing could not exclude maternal inheritance), was present at low frequency in gnomAD, and showed no functional impact in Drosophila modelling — consistent with VUS rather than pathogenic classification. Of the 4/5 missense variants modelled using the fly fry ortholog, only 1 showed severe loss-of-function, 2 showed partial LoF, and 1 showed no effect, providing mixed functional support. Key concerns limiting confidence: (1) Half of the reported variants (7) are present in gnomAD v4.1.1. (2) gnomAD v4.1.1 shows numerous NMD-predicted variants distributed throughout FRYL, inconsistent with the proposed LoF-intolerance/ haploinsufficiency mechanism. (3) All the reported variants have an overall germline classification of 'Conflicting' or 'Uncertain significance' in ClinVar. (4) The fly model uses a single fry ortholog, whereas humans have two paralogs (FRY and FRYL), limiting translatability to human-specific FRYL disease (5) No familial segregation data exist (all cases simplex). (6) High rate of co-occurring candidate variants in other genes (8/14) confounds phenotype attribution. This gene has been associated with Pan-Chung-Bellen syndrome in OMIM (MIM #621049), which was last accessed on 02 September 2026. This gene is rated with 'moderate' rating on the DD panel of Gene2Phenotype, with amber rating on relevant panels in PanelApp Australia and has not been associated with any phenotypes in ClinGen. This gene is also rated amber on the Intellectual disability and Fetal anomalies panels in Genomics England PanelApp. Overall, this represents a single-publication gene-disease claim with substantive unresolved population genetics and functional modelling concerns — further independent case series and reconciliation with gnomAD v4 constraint data are needed before upgrading to green.; to: PMID:38479391 (2024) reported 14 unrelated individuals with heterozygous FRYL variants (5 missense, 8 frameshift/stop-gain, 1 canonical splice) presenting with developmental delay/intellectual disability, dysmorphic features, and variable congenital anomalies across multiple systems. DD/ID was the only universal feature (14/14); all other phenotypes were variable and nonspecific, and 8/14 individuals harboured additional P/LP variants (in SF3B4, DHCR7, SLC6A19, SDHA) or VUSs in other genes that could partially confound phenotype attribution. Thirteen of 14 variants were confirmed de novo; the remaining variant (p.Ser2397Ile) was not confirmed de novo (duo testing could not exclude maternal inheritance), was present at low frequency in gnomAD, and showed no functional impact in Drosophila modelling — consistent with VUS rather than pathogenic classification. Of the 4/5 missense variants modelled using the fly fry ortholog, only 1 showed severe loss-of-function, 2 showed partial LoF, and 1 showed no effect, providing mixed functional support. Key concerns limiting confidence: (1) Half of the reported variants (7) are present in gnomAD v4.1.1. (2) gnomAD v4.1.1 shows numerous NMD-predicted variants distributed throughout FRYL, inconsistent with the proposed LoF-intolerance/ haploinsufficiency mechanism. (3) All the reported variants have an overall germline classification of 'Conflicting' or 'Uncertain significance' in ClinVar. (4) The fly model uses a single fry ortholog, whereas humans have two paralogs (FRY and FRYL), limiting translatability to human-specific FRYL disease (5) No familial segregation data exist (all cases simplex). (6) High rate of co-occurring candidate variants in other genes (8/14) confounds phenotype attribution. This gene has been associated with Pan-Chung-Bellen syndrome in OMIM (MIM #621049), which was last accessed on 02 September 2026. This gene is rated with 'moderate' rating on the DD panel of Gene2Phenotype, with amber rating on relevant panels in PanelApp Australia and has not been associated with any phenotypes in ClinGen. This gene is also rated amber on the Intellectual disability and Fetal anomalies panels in Genomics England PanelApp. |
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| DDG2P v8.1 | FRYL |
Achchuthan Shanmugasundram edited their review of gene: FRYL: Added comment: PMID:38479391 (2024) reported 14 unrelated individuals with heterozygous FRYL variants (5 missense, 8 frameshift/stop-gain, 1 canonical splice) presenting with developmental delay/intellectual disability, dysmorphic features, and variable congenital anomalies across multiple systems. DD/ID was the only universal feature (14/14); all other phenotypes were variable and nonspecific, and 8/14 individuals harboured additional P/LP variants (in SF3B4, DHCR7, SLC6A19, SDHA) or VUSs in other genes that could partially confound phenotype attribution. Thirteen of 14 variants were confirmed de novo; the remaining variant (p.Ser2397Ile) was not confirmed de novo (duo testing could not exclude maternal inheritance), was present at low frequency in gnomAD, and showed no functional impact in Drosophila modelling — consistent with VUS rather than pathogenic classification. Of the 4/5 missense variants modelled using the fly fry ortholog, only 1 showed severe loss-of-function, 2 showed partial LoF, and 1 showed no effect, providing mixed functional support. Key concerns limiting confidence: (1) Half of the reported variants (7) are present in gnomAD v4.1.1. (2) gnomAD v4.1.1 shows numerous NMD-predicted variants distributed throughout FRYL, inconsistent with the proposed LoF-intolerance/ haploinsufficiency mechanism. (3) All the reported variants have an overall germline classification of 'Conflicting' or 'Uncertain significance' in ClinVar. (4) The fly model uses a single fry ortholog, whereas humans have two paralogs (FRY and FRYL), limiting translatability to human-specific FRYL disease (5) No familial segregation data exist (all cases simplex). (6) High rate of co-occurring candidate variants in other genes (8/14) confounds phenotype attribution. This gene has been associated with Pan-Chung-Bellen syndrome in OMIM (MIM #621049), which was last accessed on 02 September 2026. This gene is rated with 'moderate' rating on the DD panel of Gene2Phenotype, with amber rating on relevant panels in PanelApp Australia and has not been associated with any phenotypes in ClinGen. This gene is also rated amber on the Intellectual disability and Fetal anomalies panels in Genomics England PanelApp. Overall, this represents a single-publication gene-disease claim with substantive unresolved population genetics and functional modelling concerns — further independent case series and reconciliation with gnomAD v4 constraint data are needed before upgrading to green.; Changed phenotypes to: Pan-Chung-Bellen syndrome, OMIM:621049, Pan-Chung-Bellen syndrome, MONDO:0975953, FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities |
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| DDG2P v3.12 | SF3B4 | Achchuthan Shanmugasundram reviewed gene: SF3B4: Rating: GREEN; Mode of pathogenicity: ; Publications: 22541558; Phenotypes: ACROFACIAL DYSOSTOSIS 1, NAGER TYPE, OMIM:154400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v0.2 | SF3B4 | Rebecca Foulger reviewed gene: SF3B4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v0.1 | SF3B4 |
Rebecca Foulger gene: SF3B4 was added gene: SF3B4 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype Mode of inheritance for gene: SF3B4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SF3B4 were set to 22541558 Phenotypes for gene: SF3B4 were set to ACROFACIAL DYSOSTOSIS 1, NAGER TYPE 154400 |
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