rs132630273

Positions:

• chrX-48684284-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000377.3(WAS):​c.134C>T​(p.Thr45Met) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 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).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: WAS NM_000377.3 missense, splice_region
• Scores: Splicing: ADA: 0.5609
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 3.90

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant X-48684284-C-T is Pathogenic according to our data. Variant chrX-48684284-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 11123.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WAS	NM_000377.3	c.134C>T	p.Thr45Met	missense_variant, splice_region_variant	2/12	ENST00000376701.5	NP_000368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WAS	ENST00000376701.5	c.134C>T	p.Thr45Met	missense_variant, splice_region_variant	2/12	1	NM_000377.3	ENSP00000365891.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1098205 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363565

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombocytopenia 1 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 08, 2023	Variant summary: WAS c.134C>T (p.Thr45Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182571 control chromosomes (gnomAD). c.134C>T has been reported in the literature in the hemizygous state in multiple male individuals affected with X-Linked Thrombocytopenia, including at least one family in which the variant segregated with the disease phenotype (e.g. Kwan_1995, de Saint Basile_1996, Ho_2001). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant partially impairs binding with WIP, an interaction proposed as causal to the disease (e.g. Rajmohan_2009). Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 19817875, 23160469). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 0.66). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011123). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11167787, 12969986, 15284122, 21185603, 28641574, 7753869, 8757563, 9326235). A different missense change at the same codon (p.Thr45Lys) has been reported to be associated with WAS related disorder (PMID: 20546529). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Wiskott-Aldrich syndrome;C1839163:Thrombocytopenia 1;C1845987:X-linked severe congenital neutropenia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 18, 2023	Experimental studies have shown that this missense change affects WAS function (PMID: 19817875, 23160469). For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 11123). This variant is also known as 168C>T. This missense change has been observed in individual(s) with Wiskott-Aldrich syndrome (PMID: 7753869, 8757563, 9326235, 11167787, 12969986, 15284122, 21185603, 28641574). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 45 of the WAS protein (p.Thr45Met). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 06, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2023	Published functional studies demonstrate a damaging effect; reduces protein stability and ability to bind WIP (Worth et al., 2013); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 8757563, 34705590, 31064749, 23160469, 11167787, 7753869, 28641574, 19817875, 31677488, 32814211, 35874699) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	WAS: PP1:Strong, PM2, PM5, PS4:Moderate, PS3:Supporting -

WAS-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2024

The WAS c.134C>T variant is predicted to result in the amino acid substitution p.Thr45Met. This variant has been reported as causative for Wiskott-Aldrich syndrome (see for examples Kwan et al. 1995. PubMed ID: 7753869; Jin et al. 2004. PubMed ID: 15284122; Gulácsy et al. 2011. PubMed ID: 21185603). Functional studies indicate this variant decreases protein function (Worth et al. 2013. PubMed ID: 23160469). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/11123). Given the evidence, we interpret c.134C>T (p.Thr45Met) as pathogenic. -

Wiskott-Aldrich syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

May 20, 2023

The observed missense c.134C>T(p.Thr45Met) variant in WAS gene has been reported previously in X-linked state in individual(s) affected with Wiskott-Aldrich syndrome (Yue et al., 2022). This variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). The amino acid Thr at position 45 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Thr45Met in WAS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging, and MutationTaster - Disease causing automatic) predict a damaging effect on protein structure and function for this variant. Experimental evidence indicated an impact on protein function and found that the variant partially impairs binding with WIP, an interaction proposed as causal to the disease (Rajmohan et al., 2009). For these reasons, this variant has been classified as Pathogenic. -

Thrombocytopenia Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;D
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	.;D
Vest4		0.85
MutPred		0.86		Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.84
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.56
dbscSNV1_RF	Benign	0.71
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

Other links and lift over

dbSNP: rs132630273; hg19: chrX-48542673; COSMIC: COSV64997200; COSMIC: COSV64997200;