rs1557006354

chrX-48684421-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PM2 PP3 PP5_Moderate

The NM_000377.3(WAS):c.271C>T(p.Gln91Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Q91Q) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 21)
• Consequence: WAS NM_000377.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9982
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.29

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 13 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-48684421-C-T is Pathogenic according to our data. Variant chrX-48684421-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 528221.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WAS	NM_000377.3	c.271C>T	p.Gln91Ter	stop_gained, splice_region_variant	2/12	ENST00000376701.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WAS	ENST00000376701.5	c.271C>T	p.Gln91Ter	stop_gained, splice_region_variant	2/12	1	NM_000377.3	P2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2017

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in WAS are known to be pathogenic (PMID: 15284122). This variant has not been reported in the literature in individuals with WAS-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln91*) in the WAS gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	37
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A
Vest4		0.35
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.090		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: rs1557006354; hg19: chrX-48542810;