rs139265251

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 4P and 13B. PM1PM5BP4_StrongBP6BS1BS2

The NM_000377.3(WAS):c.413G>A(p.Arg138Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000718 in 1,182,649 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 269 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R138W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., 26 hem., cov: 23)

Exomes 𝑓: 0.00072 ( 0 hom. 243 hem. )

Consequence

WAS
NM_000377.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:1

Conservation

PhyloP100: -0.126

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

Wiskott-Aldrich syndrome
Inheritance: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
X-linked severe congenital neutropenia
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
thrombocytopenia 1
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

WAS links:

ENSG00000232828 (HGNC:):

ENSG00000232828 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000377.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-48685786-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 495847.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.01782313).

BP6

Variant X-48685786-G-A is Benign according to our data. Variant chrX-48685786-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135414.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000723 (81/112015) while in subpopulation AMR AF = 0.00104 (11/10577). AF 95% confidence interval is 0.000765. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 81 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WAS	NM_000377.3 link	c.413G>A	p.Arg138Gln	missense_variant	Exon 4 of 12	ENST00000376701.5	NP_000368.1	P42768A0A024QYX8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WAS	ENST00000376701.5 link	c.413G>A	p.Arg138Gln	missense_variant	Exon 4 of 12	1	NM_000377.3	ENSP00000365891.4		P42768

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

AN:

111963

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000651

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.00104

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000844

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000978

Gnomad OTH

AF:

0.000668

GnomAD2 exomes

AF:

0.000451

AC:

AN:

135281

AF XY:

0.000491

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000361

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000295

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000868

Gnomad OTH exome

AF:

0.000542

GnomAD4 exome

AF:

0.000717

AC:

768

AN:

1070634

Hom.:

Cov.:

AF XY:

0.000697

AC XY:

243

AN XY:

348606

show subpopulations

African (AFR)

AF:

0.0000782

AC:

AN:

25585

American (AMR)

AF:

0.000423

AC:

AN:

30727

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18958

East Asian (EAS)

AF:

0.000352

AC:

AN:

28413

South Asian (SAS)

AF:

0.0000390

AC:

AN:

51295

European-Finnish (FIN)

AF:

0.000129

AC:

AN:

38701

Middle Eastern (MID)

AF:

0.000487

AC:

AN:

4106

European-Non Finnish (NFE)

AF:

0.000853

AC:

706

AN:

827814

Other (OTH)

AF:

0.000622

AC:

AN:

45035

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

124

166

207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000723

AC:

AN:

112015

Hom.:

Cov.:

AF XY:

0.000760

AC XY:

AN XY:

34207

show subpopulations

African (AFR)

AF:

0.0000649

AC:

AN:

30812

American (AMR)

AF:

0.00104

AC:

AN:

10577

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.000847

AC:

AN:

3544

South Asian (SAS)

AF:

0.00

AC:

AN:

2703

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6131

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000978

AC:

AN:

53187

Other (OTH)

AF:

0.000659

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000797

Hom.:

Bravo

AF:

0.000748

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00134

AC:

ExAC

AF:

0.000434

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Wiskott-Aldrich syndrome

Uncertain:1

Aug 19, 2020

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

WAS-related disorder

Benign:1

Jun 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

WAS: BS2 -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

8.7

(source)

DANN

Benign

0.92

DEOGEN2

Uncertain

0.48

T;D

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.66

T;T

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.018

T;T

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

0.16

.;N

PhyloP100

-0.13

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.7

N;N

REVEL

Uncertain

0.36

Sift

Benign

0.32

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.27

.;B

Vest4

0.13

MVP

0.81

MPC

0.68

ClinPred

0.015

GERP RS

-3.7

Varity_R

0.082

gMVP

0.68

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over