X-48688936-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000377.3(WAS):c.1208C>T(p.Pro403Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,161,662 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P403P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000050 ( 0 hom. 14 hem. )

Consequence

WAS
NM_000377.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 2.11

Publications

1 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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 6 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WAS	NM_000377.3 link	c.1208C>T	p.Pro403Leu	missense_variant	Exon 10 of 12	ENST00000376701.5	NP_000368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WAS	ENST00000376701.5 link	c.1208C>T	p.Pro403Leu	missense_variant	Exon 10 of 12	1	NM_000377.3	ENSP00000365891.4

Frequencies

GnomAD3 genomes

AF:

0.0000539

AC:

AN:

111346

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000114

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000294

AC:

AN:

102209

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000116

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000525

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000505

AC:

AN:

1050316

Hom.:

Cov.:

AF XY:

0.0000415

AC XY:

AN XY:

337698

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25231

American (AMR)

AF:

0.00

AC:

AN:

28272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17810

East Asian (EAS)

AF:

0.00

AC:

AN:

27711

South Asian (SAS)

AF:

0.0000207

AC:

AN:

48406

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3501

European-Non Finnish (NFE)

AF:

0.0000636

AC:

AN:

818068

Other (OTH)

AF:

0.00

AC:

AN:

44201

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000539

AC:

AN:

111346

Hom.:

Cov.:

AF XY:

0.0000597

AC XY:

AN XY:

33520

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30604

American (AMR)

AF:

0.00

AC:

AN:

10607

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3516

South Asian (SAS)

AF:

0.00

AC:

AN:

2661

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000114

AC:

AN:

52798

Other (OTH)

AF:

0.00

AC:

AN:

1482

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000173310), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000480

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000182

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Mar 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 04, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PS4_supporting -

Jan 16, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34390440, 28748566) -

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

Uncertain:1Benign:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

WAS-related disorder

Uncertain:1

May 29, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The WAS c.1208C>T variant is predicted to result in the amino acid substitution p.Pro403Leu. This variant was reported in an individual with Thrombocytopaenia (Leinøe et al 2017. PubMed ID: 28748566, Supplementary Table 2). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-48547325-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Wiskott-Aldrich syndrome

Uncertain:1

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

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

-0.017

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Uncertain

0.64

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.69

M_CAP

Pathogenic

0.92

MetaRNN

Uncertain

0.48

MetaSVM

Pathogenic

0.98

MutationAssessor

Benign

1.8

PhyloP100

2.1

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.48

Sift

Benign

0.11

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.28

MutPred

0.32

Loss of glycosylation at P403 (P = 8e-04);

MVP

0.91

MPC

0.59

ClinPred

0.27

GERP RS

4.6

Varity_R

0.18

gMVP

0.089

Mutation Taster

=16/84

disease causing

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over