rs139265251

Variant summary

Our verdict is Benign. Variant got -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. 12/19 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. R138P) has been classified as Pathogenic.

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:2O:1

Conservation

PhyloP100: -0.126

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 -9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 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 id 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 id is 135414.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_benign=1, Benign=1}. Variant chrX-48685786-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WAS	NM_000377.3 linkuse as main transcript	c.413G>A	p.Arg138Gln	missense_variant	4/12	ENST00000376701.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WAS	ENST00000376701.5 linkuse as main transcript	c.413G>A	p.Arg138Gln	missense_variant	4/12	1	NM_000377.3	P2

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

AN:

111963

Hom.:

Cov.:

AF XY:

0.000761

AC XY:

AN XY:

34145

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

GnomAD3 exomes

AF:

0.000451

AC:

AN:

135281

Hom.:

AF XY:

0.000491

AC XY:

AN XY:

42729

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.0000782

Gnomad4 AMR exome

AF:

0.000423

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000352

Gnomad4 SAS exome

AF:

0.0000390

Gnomad4 FIN exome

AF:

0.000129

Gnomad4 NFE exome

AF:

0.000853

Gnomad4 OTH exome

AF:

0.000622

GnomAD4 genome

AF:

0.000723

AC:

AN:

112015

Hom.:

Cov.:

AF XY:

0.000760

AC XY:

AN XY:

34207

show subpopulations

Gnomad4 AFR

AF:

0.0000649

Gnomad4 AMR

AF:

0.00104

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000847

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000978

Gnomad4 OTH

AF:

0.000659

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:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Wiskott-Aldrich syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 19, 2020

- -

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

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

WAS: BS2 -

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

0.059

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

Cadd

Benign

8.7

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

MutationTaster

Benign

1.0

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

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