X-48683854-A-T

Position:

• chrX-48683854-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000377.3(WAS):​c.1A>T​(p.Met1?) variant causes a start lost 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: WAS NM_000377.3 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.19

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 11 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-48683854-A-T is Pathogenic according to our data. Variant chrX-48683854-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 11120.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WAS	NM_000377.3	c.1A>T	p.Met1?	start_lost	1/12	ENST00000376701.5	NP_000368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WAS	ENST00000376701.5	c.1A>T	p.Met1?	start_lost	1/12	1	NM_000377.3	ENSP00000365891	P2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Wiskott-Aldrich syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2006

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Benign	22
DANN	Benign	0.87
DEOGEN2	Benign	0.0066	T;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.97	D
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-0.76	N;N
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0	.;B
Vest4		0.88
MutPred		1.0		Loss of MoRF binding (P = 0.0958);Loss of MoRF binding (P = 0.0958);
MVP		1.0
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.91
gMVP		0.70

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: rs587776742; hg19: chrX-48542243;