chrX-48684323-C-G

Position:

• chrX-48684323-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The ENST00000376701.5(WAS):​c.173C>G​(p.Pro58Arg) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P58H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: WAS ENST00000376701.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.98

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.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in ENST00000376701.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-48684323-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420291.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant X-48684323-C-G is Pathogenic according to our data. Variant chrX-48684323-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 11126.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.173C>G	p.Pro58Arg	missense_variant	2/12	ENST00000376701.5	NP_000368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WAS	ENST00000376701.5	c.173C>G	p.Pro58Arg	missense_variant	2/12	1	NM_000377.3	ENSP00000365891	P2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Thrombocytopenia, X-linked, intermittent Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 15, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.62
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;D
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.67	T;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.7	.;M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.86
Sift	Benign	0.44	T;T
Sift4G	Uncertain	0.056	T;T
Polyphen		1.0	.;D
Vest4		0.92
MutPred		0.86		Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);
MVP		1.0
MPC		1.6
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.68
gMVP		0.98

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: rs132630275; hg19: chrX-48542712;