rs1557006239

Variant names:

• chrX-48683944-G-A
• rs1557006239
• NM_000377.3:c.91G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000377.3(WAS):​c.91G>A​(p.Glu31Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: WAS NM_000377.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.36
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Wiskott-Aldrich syndrome

  Inheritance: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• X-linked severe congenital neutropenia

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• thrombocytopenia 1

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000232828 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000377.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant X-48683944-G-A is Pathogenic according to our data. Variant chrX-48683944-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 528222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WAS	NM_000377.3	c.91G>A	p.Glu31Lys	missense_variant	Exon 1 of 12	ENST00000376701.5	NP_000368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WAS	ENST00000376701.5	c.91G>A	p.Glu31Lys	missense_variant	Exon 1 of 12	1	NM_000377.3	ENSP00000365891.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Feb 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 31 of the WAS protein (p.Glu31Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Wiskott-Aldrich syndrome (PMID: 8528198, 8682510, 11442475, 15284122, 21185603, 22523910, 25476427, 25792466, 28623282). In at least one individual the variant was observed to be de novo. This variant is also known as c.125G>A. ClinVar contains an entry for this variant (Variation ID: 528222). 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) performed at Invitae indicates that this missense variant is not expected to disrupt WAS protein function. Experimental studies have shown that this missense change affects WAS function (PMID: 19817875). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

May 17, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The E31K variant has been published previously in association with Wiskott-Aldrich syndrome (Kolluri et al., 1995; Ariga et al., 1997). The variant is not observed in large population cohorts (Lek et al., 2016). E31K is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, functional studies have shown E31K damages the ability of the WAS protein to bind WIP (Rajmohan et al., 2009). In summary, this variant is likely pathogenic. -

Wiskott-Aldrich syndrome Pathogenic:1

Apr 03, 2024

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 31 of the WAS protein (p.Glu31Lys). Experimental studies have shown that this missense change affects WAS function (PMID: 19817875). 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) performed at Invitae indicates that this missense variant is not expected to disrupt WAS protein function. ClinVar contains an entry for this variant (Variation ID: 528222). This variant is also known as c.125G>A. This missense change has been observed in individual(s) with Wiskott-Aldrich syndrome (PMID: 8528198, 8682510, 11442475, 15284122, 21185603, 22523910, 25476427, 25792466, 28623282). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.70
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.5	.;M
PhyloP100		6.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.68
MutPred		0.90		Gain of ubiquitination at E31 (P = 0.0114);Gain of ubiquitination at E31 (P = 0.0114);
MVP		1.0
MPC		1.6
ClinPred		0.99	D
GERP RS		4.3
PromoterAI		-0.018	Neutral
Varity_R		0.97
gMVP		1.0
Mutation Taster		=34/66	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1557006239; hg19: chrX-48542333;