X-48688994-CG-CGG

Variant names:

• chrX-48688994-C-CG
• rs1557007312
• NM_000377.3:c.1271dupG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000377.3(WAS):​c.1271dupG​(p.Leu425ProfsTer70) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: WAS NM_000377.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.466

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-48688994-C-CG is Pathogenic according to our data. Variant chrX-48688994-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 495844.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.1271dupG	p.Leu425ProfsTer70	frameshift_variant	Exon 10 of 12	ENST00000376701.5	NP_000368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WAS	ENST00000376701.5	c.1271dupG	p.Leu425ProfsTer70	frameshift_variant	Exon 10 of 12	1	NM_000377.3	ENSP00000365891.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombocytopenia 1 Pathogenic:1

Feb 11, 2020

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A hemizygous single base pair deletion in exon 10 of the WAS gene that results in a frameshift and premature truncation of the protein 70 amino acids downstream to codon 425 was detected. The observed variant c.1266_1267insG (p.Leu425ProfsTer) has not been reported in the 1000 Genomes and ExAC databases. The in silico prediction of the variant is damaging by MutationTaster2. The observed variant has previously been reported in patients affected with thrombocytopenia (Kolluri et al 1995) and has been reported as pathogenic in ClinVar database. The reference codon is conserved across primates. In summary, the variant meets our criteria to be classified as pathogenic. -

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

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu425Profs*70) in the WAS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 78 amino acid(s) of the WAS protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Wiskott-Aldrich syndrome (PMID: 8528198, 11442475, 12727931, 24210885). This variant is also known as G insertion after G13O5, 1271insG, and 1305insG. ClinVar contains an entry for this variant (Variation ID: 495844). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects WAS function (PMID: 11442475, 12727931). For these reasons, this variant has been classified as Pathogenic. -

Wiskott-Aldrich syndrome Pathogenic:1

Aug 10, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The WAS c.1271dupG (p.Leu425Profs) variant results in a premature termination codon, predicted to cause a truncated or absent WAS protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as likely pathogenic by our laboratory (e.g. c.1352delC, p.Pro451fs). MutationTaster predicts a damaging outcome for this variant. Functional studies showed absent or very low WASP protein levels in PBMCs and T lymphocytes derived from Wiskott-Aldrich syndrome patients (Qasim_2001, Wada_2003). This variant was not found in the large control database ExAC in 30090 control chromosomes and was found in several male patients with Wiskott-Aldrich syndrome (Qasim_2001, Wada_2003, Kolluri_1995, Simon_2014). Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1557007312; hg19: chrX-48547383;