rs782290433
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000377.3(WAS):c.223G>A(p.Val75Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000895 in 111,733 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000377.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WAS | NM_000377.3 | c.223G>A | p.Val75Met | missense_variant | Exon 2 of 12 | ENST00000376701.5 | NP_000368.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000895 AC: 1AN: 111682Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33838
GnomAD3 exomes AF: 0.00000549 AC: 1AN: 182289Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 66823
GnomAD4 exome Cov.: 32
GnomAD4 genome AF: 0.00000895 AC: 1AN: 111733Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33899
ClinVar
Submissions by phenotype
Wiskott-Aldrich syndrome;C1839163:Thrombocytopenia 1;C1845987:X-linked severe congenital neutropenia Pathogenic:3
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WAS NM_000377.2 exon 2 p.Val75Met (c.223G>A): This variant has been reported in the literature in >10 individuals with X-linked thrombocytopenia (Kolluri 1995 PMID:8528198 (using alternate nomenclature c.257G>A), Albert 2010 PMID:20173115, Leblebisatan 2011 PMID:27264129). This variant is present in 1/12157 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs782290433). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar (Variation ID:265289). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant (Albert 2010 PMID:20173115, Sarkar 2015 PMID:26261240). In summary, this variant is classified as pathogenic. -
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 75 of the WAS protein (p.Val75Met). This variant is present in population databases (rs782290433, gnomAD 0.008%). This missense change has been observed in individuals with X-linked thrombocytopenia (XLT) (PMID: 8528198, 8528199, 8595430, 9326235, 11793485, 12969986, 15284122, 20173115, 21185603, 27264129, 28931895). It has also been observed to segregate with disease in related individuals. This variant is also known as c.257G>A. ClinVar contains an entry for this variant (Variation ID: 265289). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WAS protein function. Experimental studies have shown that this missense change affects WAS function (PMID: 19817875, 26261240). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
The V75M missense variant in the WAS gene has been reported previously in association with WAS-related disorders (Albert et al., 2010; Kolluri et al., 1995). Please note, the Kolluri paper uses alternative cDNA nomenclature and indicates the position of the G>A nucleotide substitution at c.257. The V75M variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position within the WH1 domain that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that V75M causes a severe negative effect on WAS protein function by interfering with WAS SUMOylation (Sarkar et al., 2015). Missense variants in the same codon (V75L) and in nearby residues (C73R/Y, F74S, K76T, D77H/G) have been reported in the Human Gene Mutation Database in association with WAS-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is pathogenic. -
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Thrombocytopenia 1 Pathogenic:1
Variant summary: The WAS c.223G>A (p.Val75Met) variant located in the WASP family, EVH1 domain (via InterPro) involves the alteration of a non-conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured here due to low reliability index) predict a damaging outcome. Functional studies, Rajmohan_2009 and Sarkar_2015, indicate that the varaint does impact WAS protein functionality. This variant was found in 1/80511 control chromosomes at a frequency of 0.0000124, which does not exceed the estimated maximal expected allele frequency of a pathogenic WAS variant (0.0035355). The variant of interest has been reported in multiple affected individuals diagnosed with X-linked thrombocytopenia. In addition, a clinical diagnostic laboratory classifies this variant as pathogenic. Furthermore, additional variants affecting the same amino acid, c.223G>T (p.V75L), and surrounding, c.221T>C (p.F74S), c.227A>C (p.K76T), and c.218G>A (p.C73Y), have all been reported and classified as pathogenic, suggesting the variant resides in a mutational hotspot. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "pathogenic." -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at