NM_025132.4:c.1477G>C
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_025132.4(WDR19):c.1477G>C(p.Asp493His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000311 in 1,609,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D493D) has been classified as Uncertain significance.
Frequency
Consequence
NM_025132.4 missense, splice_region
Scores
Clinical Significance
Conservation
Publications
- asphyxiating thoracic dystrophy 5Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
- ciliopathyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- cranioectodermal dysplasia 4Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
- nephronophthisis 13Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- Senior-Loken syndrome 8Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- cranioectodermal dysplasiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Jeune syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- nephronophthisis 1Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Senior-Loken syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000406 AC: 1AN: 246460 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1457432Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 724622 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Nephronophthisis 13 Pathogenic:1
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Senior-Loken syndrome 8 Pathogenic:1
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not provided Uncertain:1
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in the heterozygous state in a patient with nonsyndromic retinitis pigmentosa, however, this individual was also homozygous for another variant in WDR19 (Coussa et al., 2013); This variant is associated with the following publications: (PMID: 23559409, 23683095, 31589614) -
Asphyxiating thoracic dystrophy 5;C4225376:Senior-Loken syndrome 8 Uncertain:1
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 493 of the WDR19 protein (p.Asp493His). This variant is present in population databases (rs587777349, gnomAD 0.0009%). This missense change has been observed in individuals with WDR19-related conditions (PMID: 23559409, 33532864; internal data). ClinVar contains an entry for this variant (Variation ID: 127155). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt WDR19 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at