rs143885622

Variant names:

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.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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P460R) has been classified as Uncertain significance.

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

Publications

9 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 -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 VariationId is 135411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 197 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WAS	NM_000377.3 link	c.1378C>T	p.Pro460Ser	missense_variant	Exon 11 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.1378C>T	p.Pro460Ser	missense_variant	Exon 11 of 12	1	NM_000377.3	ENSP00000365891.4		P42768

Frequencies

GnomAD3 genomes

AF:

0.00179

AC:

199

AN:

111378

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00343

AC:

603

AN:

175583

AF XY:

0.00340

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 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

African (AFR)

AF:

0.000114

AC:

AN:

26387

American (AMR)

AF:

0.000428

AC:

AN:

35043

Ashkenazi Jewish (ASJ)

AF:

0.00280

AC:

AN:

19320

East Asian (EAS)

AF:

0.0291

AC:

878

AN:

30159

South Asian (SAS)

AF:

0.00112

AC:

AN:

53474

European-Finnish (FIN)

AF:

0.000149

AC:

AN:

40325

Middle Eastern (MID)

AF:

0.000727

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.00134

AC:

1128

AN:

841292

Other (OTH)

AF:

0.00204

AC:

AN:

45999

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

188

282

376

470

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.00177

AC:

197

AN:

111431

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

AN XY:

33621

show subpopulations

African (AFR)

AF:

0.0000979

AC:

AN:

30643

American (AMR)

AF:

0.000854

AC:

AN:

10544

Ashkenazi Jewish (ASJ)

AF:

0.00189

AC:

AN:

2647

East Asian (EAS)

AF:

0.0307

AC:

108

AN:

3513

South Asian (SAS)

AF:

0.00113

AC:

AN:

2647

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5999

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00123

AC:

AN:

53017

Other (OTH)

AF:

0.00264

AC:

AN:

1518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.00253

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

Aug 01, 2018

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

not provided

Benign:3

Dec 05, 2014

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 15, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Wiskott-Aldrich syndrome

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

1.1

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

Mutation Taster

=97/3

polymorphism (auto)

(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