rs782290433

Positions:

chrX-48684373-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_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

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 22)

Consequence

WAS
NM_000377.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 5.46

Variant links:

Genes affected

WAS (HGNC:12731): (WASP actin nucleation promoting factor) The Wiskott-Aldrich syndrome (WAS) family of proteins share similar domain structure, and are involved in transduction of signals from receptors on the cell surface to the actin cytoskeleton. The presence of a number of different motifs suggests that they are regulated by a number of different stimuli, and interact with multiple proteins. Recent studies have demonstrated that these proteins, directly or indirectly, associate with the small GTPase, Cdc42, known to regulate formation of actin filaments, and the cytoskeletal organizing complex, Arp2/3. Wiskott-Aldrich syndrome is a rare, inherited, X-linked, recessive disease characterized by immune dysregulation and microthrombocytopenia, and is caused by mutations in the WAS gene. The WAS gene product is a cytoplasmic protein, expressed exclusively in hematopoietic cells, which show signalling and cytoskeletal abnormalities in WAS patients. A transcript variant arising as a result of alternative promoter usage, and containing a different 5' UTR sequence, has been described, however, its full-length nature is not known. [provided by RefSeq, Jul 2008]

WAS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a domain WH1 (size 109) in uniprot entity WASP_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000377.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant X-48684373-G-A is Pathogenic according to our data. Variant chrX-48684373-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 265289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48684373-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WAS	NM_000377.3 linkuse as main transcript	c.223G>A	p.Val75Met	missense_variant	2/12	ENST00000376701.5	NP_000368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WAS	ENST00000376701.5 linkuse as main transcript	c.223G>A	p.Val75Met	missense_variant	2/12	1	NM_000377.3	ENSP00000365891	P2

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111682

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33838

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000549

AC:

AN:

182289

Hom.:

AF XY:

0.00

AC XY:

AN XY:

66823

show subpopulations

Gnomad AFR exome

AF:

0.0000765

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111733

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33899

show subpopulations

Gnomad4 AFR

AF:

0.0000326

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00209

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wiskott-Aldrich syndrome;C1839163:Thrombocytopenia 1;C1845987:X-linked severe congenital neutropenia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Sep 17, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	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

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 20, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2016	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. -

Thrombocytopenia 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 05, 2017

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.67

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;D

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

.;M

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.7

D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

.;D

Vest4

0.81

MutPred

0.92

Loss of methylation at K76 (P = 0.0286);Loss of methylation at K76 (P = 0.0286);

MVP

1.0

MPC

1.6

ClinPred

0.95

GERP RS

4.7

Varity_R

0.92

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over