dbSNP rs2737799: WAS:p.Val332Ala (chrX-48688723-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:10O:1

Conservation

PhyloP100: -0.0120

Publications

10 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
X-linked severe congenital neutropenia
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -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 Benign/Likely_benign. ClinVar VariationId is 135410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 536 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000377.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WAS	NM_000377.3	MANE Select	c.995T>C	p.Val332Ala	missense	Exon 10 of 12	NP_000368.1	P42768
WAS	NM_001438877.1		c.995T>C	p.Val332Ala	missense	Exon 10 of 12	NP_001425806.1
WAS	NM_001438879.1		c.995T>C	p.Val332Ala	missense	Exon 11 of 13	NP_001425808.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WAS	ENST00000376701.5	TSL:1 MANE Select	c.995T>C	p.Val332Ala	missense	Exon 10 of 12	ENSP00000365891.4	P42768
WAS	ENST00000698635.1		c.995T>C	p.Val332Ala	missense	Exon 10 of 12	ENSP00000513850.1	A0A8V8TM35
WAS	ENST00000698626.1		c.995T>C	p.Val332Ala	missense	Exon 10 of 13	ENSP00000513845.1	A0A8V8TNH9

Frequencies

GnomAD3 genomes

AF:

0.00492

AC:

536

AN:

108934

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00479

AC:

697

AN:

145484

AF XY:

0.00450

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 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

African (AFR)

AF:

0.00129

AC:

AN:

25597

American (AMR)

AF:

0.00604

AC:

192

AN:

31773

Ashkenazi Jewish (ASJ)

AF:

0.00553

AC:

AN:

17165

East Asian (EAS)

AF:

0.00

AC:

AN:

29940

South Asian (SAS)

AF:

0.00179

AC:

AN:

49264

European-Finnish (FIN)

AF:

0.00785

AC:

307

AN:

39093

Middle Eastern (MID)

AF:

0.0155

AC:

AN:

3287

European-Non Finnish (NFE)

AF:

0.00590

AC:

4872

AN:

826341

Other (OTH)

AF:

0.00624

AC:

278

AN:

44570

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

216

432

648

864

1080

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

360

540

720

900

<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:

0.00492

AC:

536

AN:

108981

Hom.:

Cov.:

AF XY:

0.00419

AC XY:

132

AN XY:

31479

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

29826

American (AMR)

AF:

0.00788

AC:

AN:

10404

Ashkenazi Jewish (ASJ)

AF:

0.00539

AC:

AN:

2598

East Asian (EAS)

AF:

0.00

AC:

AN:

3431

South Asian (SAS)

AF:

0.00204

AC:

AN:

2446

European-Finnish (FIN)

AF:

0.00713

AC:

AN:

5888

Middle Eastern (MID)

AF:

0.00930

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00669

AC:

348

AN:

52027

Other (OTH)

AF:

0.00673

AC:

AN:

1486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

101

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:

0.00605

Hom.:

281

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (5)

Wiskott-Aldrich syndrome (2)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

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

PhyloP100

-0.012

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

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over