rs146220228

Positions:

chrX-48685764-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The ENST00000376701.5(WAS):c.391G>A(p.Glu131Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,180,777 control chromosomes in the GnomAD database, including 5 homozygotes. There are 978 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., 77 hem., cov: 23)

Exomes 𝑓: 0.0027 ( 4 hom. 901 hem. )

Consequence

WAS
ENST00000376701.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8O:1

Conservation

PhyloP100: 1.61

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 -11 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in ENST00000376701.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0077780485).

BP6

Variant X-48685764-G-A is Benign according to our data. Variant chrX-48685764-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135413.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1, Likely_benign=4, not_provided=1}. Variant chrX-48685764-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00217 (244/112368) while in subpopulation NFE AF= 0.00336 (179/53264). AF 95% confidence interval is 0.00296. There are 1 homozygotes in gnomad4. There are 77 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 77 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WAS	NM_000377.3 linkuse as main transcript	c.391G>A	p.Glu131Lys	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 linkuse as main transcript	c.391G>A	p.Glu131Lys	missense_variant	4/12	1	NM_000377.3	ENSP00000365891	P2

Frequencies

GnomAD3 genomes

AF:

0.00216

AC:

243

AN:

112317

Hom.:

Cov.:

AF XY:

0.00221

AC XY:

AN XY:

34457

show subpopulations

Gnomad AFR

AF:

0.000291

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000942

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00146

Gnomad FIN

AF:

0.00619

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00336

Gnomad OTH

AF:

0.00199

GnomAD3 exomes

AF:

0.00259

AC:

344

AN:

132777

Hom.:

AF XY:

0.00222

AC XY:

AN XY:

42359

show subpopulations

Gnomad AFR exome

AF:

0.000226

Gnomad AMR exome

AF:

0.000456

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00237

Gnomad FIN exome

AF:

0.00639

Gnomad NFE exome

AF:

0.00384

Gnomad OTH exome

AF:

0.00247

GnomAD4 exome

AF:

0.00270

AC:

2883

AN:

1068409

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

901

AN XY:

348391

show subpopulations

Gnomad4 AFR exome

AF:

0.000196

Gnomad4 AMR exome

AF:

0.000427

Gnomad4 ASJ exome

AF:

0.0000529

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00268

Gnomad4 FIN exome

AF:

0.00584

Gnomad4 NFE exome

AF:

0.00288

Gnomad4 OTH exome

AF:

0.00240

GnomAD4 genome

AF:

0.00217

AC:

244

AN:

112368

Hom.:

Cov.:

AF XY:

0.00223

AC XY:

AN XY:

34518

show subpopulations

Gnomad4 AFR

AF:

0.000291

Gnomad4 AMR

AF:

0.000941

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00146

Gnomad4 FIN

AF:

0.00619

Gnomad4 NFE

AF:

0.00336

Gnomad4 OTH

AF:

0.00262

Alfa

AF:

0.00267

Hom.:

113

Bravo

AF:

0.00164

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00312

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00343

AC:

ExAC

AF:

0.00254

AC:

296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2021	This variant is associated with the following publications: (PMID: 32185379, 28008999, 27153395, 8528199, 24728327, 19817875) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	WAS: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 26, 2017	- -

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

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 13, 2022	- -

Thrombocytopenia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

- -

X-linked severe congenital neutropenia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

WAS-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Wiskott-Aldrich syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.65

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

D;D

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

D;D

MetaRNN

Benign

0.0078

T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

.;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.028

D;D

Polyphen

1.0

.;D

Vest4

0.065

MVP

1.0

MPC

1.6

ClinPred

0.033

GERP RS

4.3

Varity_R

0.56

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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