rs2737799

Positions:

chrX-48688723-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000377.3(WAS):c.995T>C(p.Val332Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00549 in 1,176,011 control chromosomes in the GnomAD database, including 17 homozygotes. There are 2,014 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V332V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0049 ( 2 hom., 132 hem., cov: 22)

Exomes 𝑓: 0.0055 ( 15 hom. 1882 hem. )

Consequence

WAS
NM_000377.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:7O:1

Conservation

PhyloP100: -0.0120

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009927154).

BP6

Variant X-48688723-T-C is Benign according to our data. Variant chrX-48688723-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 135410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48688723-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00492 (536/108981) while in subpopulation AMR AF= 0.00788 (82/10404). AF 95% confidence interval is 0.00651. There are 2 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WAS	NM_000377.3 linkuse as main transcript	c.995T>C	p.Val332Ala	missense_variant	10/12	ENST00000376701.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WAS	ENST00000376701.5 linkuse as main transcript	c.995T>C	p.Val332Ala	missense_variant	10/12	1	NM_000377.3	P2

Frequencies

GnomAD3 genomes

AF:

0.00492

AC:

536

AN:

108934

Hom.:

Cov.:

AF XY:

0.00417

AC XY:

131

AN XY:

31422

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00789

Gnomad ASJ

AF:

0.00539

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00163

Gnomad FIN

AF:

0.00713

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00669

Gnomad OTH

AF:

0.00682

GnomAD3 exomes

AF:

0.00479

AC:

697

AN:

145484

Hom.:

AF XY:

0.00450

AC XY:

209

AN XY:

46480

show subpopulations

Gnomad AFR exome

AF:

0.000633

Gnomad AMR exome

AF:

0.00554

Gnomad ASJ exome

AF:

0.00311

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00135

Gnomad FIN exome

AF:

0.00781

Gnomad NFE exome

AF:

0.00624

Gnomad OTH exome

AF:

0.00695

GnomAD4 exome

AF:

0.00554

AC:

5916

AN:

1067030

Hom.:

Cov.:

AF XY:

0.00547

AC XY:

1882

AN XY:

343934

show subpopulations

Gnomad4 AFR exome

AF:

0.00129

Gnomad4 AMR exome

AF:

0.00604

Gnomad4 ASJ exome

AF:

0.00553

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00179

Gnomad4 FIN exome

AF:

0.00785

Gnomad4 NFE exome

AF:

0.00590

Gnomad4 OTH exome

AF:

0.00624

GnomAD4 genome

AF:

0.00492

AC:

536

AN:

108981

Hom.:

Cov.:

AF XY:

0.00419

AC XY:

132

AN XY:

31479

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00788

Gnomad4 ASJ

AF:

0.00539

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00204

Gnomad4 FIN

AF:

0.00713

Gnomad4 NFE

AF:

0.00669

Gnomad4 OTH

AF:

0.00673

Alfa

AF:

0.00645

Hom.:

277

Bravo

AF:

0.00466

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.000266

AC:

ESP6500EA

AF:

0.00467

AC:

ExAC

AF:

0.00432

AC:

519

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Wiskott-Aldrich syndrome

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2021	This variant is associated with the following publications: (PMID: 27153395, 17400488, 22995991, 24728327, 24369837, 23689198) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 17, 2017	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.11

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.42

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.0099

MetaSVM

Pathogenic

0.87

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.40

REVEL

Benign

0.26

Sift

Benign

0.49

Sift4G

Benign

0.53

Polyphen

0.0

Vest4

0.027

MVP

0.78

MPC

0.70

ClinPred

0.0013

GERP RS

1.9

Varity_R

0.061

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over