rs143885622

Positions:

chrX-48689359-C-T

Variant summary

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

The NM_000377.3(WAS):c.1378C>T(p.Pro460Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,207,556 control chromosomes in the GnomAD database, including 19 homozygotes. There are 812 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., 57 hem., cov: 23)

Exomes 𝑓: 0.0020 ( 19 hom. 755 hem. )

Consequence

WAS
NM_000377.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 1.13

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:

WAS (HGNC:):

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=0.002421677).

BP6

Variant X-48689359-C-T is Benign according to our data. Variant chrX-48689359-C-T is described in ClinVar as [Benign]. Clinvar id is 135411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48689359-C-T is described in Lovd as [Benign]. Variant chrX-48689359-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00177 (197/111431) while in subpopulation EAS AF= 0.0307 (108/3513). AF 95% confidence interval is 0.026. There are 0 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 57 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WAS	NM_000377.3 linkuse as main transcript	c.1378C>T	p.Pro460Ser	missense_variant	11/12	ENST00000376701.5	NP_000368.1	P42768A0A024QYX8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WAS	ENST00000376701.5 linkuse as main transcript	c.1378C>T	p.Pro460Ser	missense_variant	11/12	1	NM_000377.3	ENSP00000365891.4		P42768

Frequencies

GnomAD3 genomes

AF:

0.00179

AC:

199

AN:

111378

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

AN XY:

33558

show subpopulations

Gnomad AFR

AF:

0.0000981

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000855

Gnomad ASJ

AF:

0.00189

Gnomad EAS

AF:

0.0312

Gnomad SAS

AF:

0.00113

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00123

Gnomad OTH

AF:

0.00267

GnomAD3 exomes

AF:

0.00343

AC:

603

AN:

175583

Hom.:

AF XY:

0.00340

AC XY:

208

AN XY:

61209

show subpopulations

Gnomad AFR exome

AF:

0.0000803

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00329

Gnomad EAS exome

AF:

0.0334

Gnomad SAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00111

Gnomad OTH exome

AF:

0.00161

GnomAD4 exome

AF:

0.00204

AC:

2241

AN:

1096125

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

755

AN XY:

361727

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.000428

Gnomad4 ASJ exome

AF:

0.00280

Gnomad4 EAS exome

AF:

0.0291

Gnomad4 SAS exome

AF:

0.00112

Gnomad4 FIN exome

AF:

0.000149

Gnomad4 NFE exome

AF:

0.00134

Gnomad4 OTH exome

AF:

0.00204

GnomAD4 genome

AF:

0.00177

AC:

197

AN:

111431

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

AN XY:

33621

show subpopulations

Gnomad4 AFR

AF:

0.0000979

Gnomad4 AMR

AF:

0.000854

Gnomad4 ASJ

AF:

0.00189

Gnomad4 EAS

AF:

0.0307

Gnomad4 SAS

AF:

0.00113

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00123

Gnomad4 OTH

AF:

0.00264

Alfa

AF:

0.00284

Hom.:

Bravo

AF:

0.00216

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00193

AC:

ExAC

AF:

0.00321

AC:

389

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 01, 2018	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 05, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2021	This variant is associated with the following publications: (PMID: 28535968, 25931402, 29358862, 30738478, 20232122, 24728327, 21185603, 22692965, 32463623, 27330000, 19775295, 25091438) -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Wiskott-Aldrich syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.29

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.98

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.18

Sift

Benign

0.074

Sift4G

Benign

0.27

Polyphen

0.041

Vest4

0.064

MVP

0.69

MPC

0.59

ClinPred

0.0051

GERP RS

1.1

Varity_R

0.053

gMVP

0.36

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

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