X-48685786-G-C

Position:

• chrX-48685786-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The ENST00000376701.5(WAS):​c.413G>C​(p.Arg138Pro) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R138Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: WAS ENST00000376701.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.126

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in ENST00000376701.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant X-48685786-G-C is Pathogenic according to our data. Variant chrX-48685786-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 495847.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WAS	NM_000377.3	c.413G>C	p.Arg138Pro	missense_variant	4/12	ENST00000376701.5	NP_000368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WAS	ENST00000376701.5	c.413G>C	p.Arg138Pro	missense_variant	4/12	1	NM_000377.3	ENSP00000365891.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thrombocytopenia 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 07, 2016

Variant summary: The WAS c.413G>C (p.Arg138Pro) variant located in the WH1/EVH1 domain (via InterPro) causes a missense change involving a non-conserved nucleotide, which 3/5 in silico tools predict a damaging outcome. Multiple functional studies support these predictions. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected indivdiuals (1 classic WAS, 2 brothers X-linked thrombocytopenia, 1 mild WAS (indicated to be de novo) via publications, which support the variability of WAS clinical manifestations. One database cites the variant as pathogenic but has not been reported by clinical diagnostic laboratories. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "pathogenic." -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D;D
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.73	T;T
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.8	.;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.59
Sift	Benign	0.056	T;T
Sift4G	Benign	0.17	T;T
Polyphen		1.0	.;D
Vest4		0.84
MutPred		0.89		Loss of MoRF binding (P = 0.0231);Loss of MoRF binding (P = 0.0231);
MVP		1.0
MPC		1.7
ClinPred		0.97	D
GERP RS		-3.7
Varity_R		0.96
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139265251; hg19: chrX-48544175;