dbSNP rs145040665: WAS:p.His180Asn (chrX-48686113-C-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001438877.1(WAS):c.538C>A(p.His180Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,210,927 control chromosomes in the GnomAD database, including 1 homozygotes. There are 546 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H180H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., 36 hem., cov: 23)

Exomes 𝑓: 0.0014 ( 1 hom. 510 hem. )

Consequence

WAS
NM_001438877.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7O:1

Conservation

PhyloP100: 1.44

Publications

5 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012371749).

BP6

Variant X-48686113-C-A is Benign according to our data. Variant chrX-48686113-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36912.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00103 (116/112767) while in subpopulation NFE AF = 0.0018 (96/53303). AF 95% confidence interval is 0.00151. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 116 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438877.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WAS	NM_000377.3	MANE Select	c.538C>A	p.His180Asn	missense	Exon 6 of 12	NP_000368.1
WAS	NM_001438877.1		c.538C>A	p.His180Asn	missense	Exon 6 of 12	NP_001425806.1
WAS	NM_001438878.1		c.538C>A	p.His180Asn	missense	Exon 6 of 12	NP_001425807.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WAS	ENST00000376701.5	TSL:1 MANE Select	c.538C>A	p.His180Asn	missense	Exon 6 of 12	ENSP00000365891.4
WAS	ENST00000698635.1		c.538C>A	p.His180Asn	missense	Exon 6 of 12	ENSP00000513850.1
WAS	ENST00000698626.1		c.538C>A	p.His180Asn	missense	Exon 6 of 13	ENSP00000513845.1

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

116

AN:

112713

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000281

Gnomad ASJ

AF:

0.00451

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000161

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00180

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00101

AC:

186

AN:

183265

AF XY:

0.00103

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.000255

Gnomad ASJ exome

AF:

0.00548

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00155

Gnomad OTH exome

AF:

0.000663

GnomAD4 exome

AF:

0.00137

AC:

1506

AN:

1098160

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

510

AN XY:

363518

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26401

American (AMR)

AF:

0.000426

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00495

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.000499

AC:

AN:

54136

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.000967

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00153

AC:

1288

AN:

842065

Other (OTH)

AF:

0.00158

AC:

AN:

46094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

117

175

234

292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.00103

AC:

116

AN:

112767

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

34919

show subpopulations

African (AFR)

AF:

0.000129

AC:

AN:

31075

American (AMR)

AF:

0.000281

AC:

AN:

10673

Ashkenazi Jewish (ASJ)

AF:

0.00451

AC:

AN:

2658

East Asian (EAS)

AF:

0.00

AC:

AN:

3606

South Asian (SAS)

AF:

0.00

AC:

AN:

2799

European-Finnish (FIN)

AF:

0.000161

AC:

AN:

6216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00180

AC:

AN:

53303

Other (OTH)

AF:

0.00

AC:

AN:

1533

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.00157

Hom.:

Bravo

AF:

0.00110

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00138

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00208

AC:

ExAC

AF:

0.000840

AC:

102

EpiCase

AF:

0.00338

EpiControl

AF:

0.00196

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Thrombocytopenia 1 (1)

WAS-related disorder (1)

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

0.077

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0077

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.61

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.012

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

1.8

PhyloP100

1.4

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.16

REVEL

Uncertain

0.41

Sift

Benign

0.48

Sift4G

Benign

0.32

Polyphen

0.48

Vest4

0.088

MVP

0.84

MPC

0.77

ClinPred

0.0080

GERP RS

4.3

Varity_R

0.15

gMVP

0.38

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.050

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