X-48684427-A-ACC

Position:

chrX-48684427-A-ACC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The ENST00000376701.5(WAS):c.273+10_273+11dup variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,193,108 control chromosomes in the GnomAD database, including 65 homozygotes. There are 792 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 5 hom., 76 hem., cov: 21)

Exomes 𝑓: 0.0021 ( 60 hom. 716 hem. )

Consequence

WAS
ENST00000376701.5 splice_donor_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0540

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 -16 ACMG points.

BP6

Variant X-48684427-A-ACC is Benign according to our data. Variant chrX-48684427-A-ACC is described in ClinVar as [Likely_benign]. Clinvar id is 36909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WAS	NM_000377.3 linkuse as main transcript	c.273+10_273+11dup		splice_donor_region_variant, intron_variant		ENST00000376701.5	NP_000368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WAS	ENST00000376701.5 linkuse as main transcript	c.273+10_273+11dup		splice_donor_region_variant, intron_variant		1	NM_000377.3	ENSP00000365891	P2

Frequencies

GnomAD3 genomes

AF:

0.00231

AC:

247

AN:

107101

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

AN XY:

30281

show subpopulations

Gnomad AFR

AF:

0.000103

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000300

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0678

Gnomad SAS

AF:

0.00246

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000135

Gnomad OTH

AF:

0.00210

GnomAD3 exomes

AF:

0.00521

AC:

842

AN:

161608

Hom.:

AF XY:

0.00472

AC XY:

244

AN XY:

51748

show subpopulations

Gnomad AFR exome

AF:

0.000177

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0637

Gnomad SAS exome

AF:

0.00191

Gnomad FIN exome

AF:

0.0000700

Gnomad NFE exome

AF:

0.000100

Gnomad OTH exome

AF:

0.00316

GnomAD4 exome

AF:

0.00210

AC:

2276

AN:

1085966

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

716

AN XY:

353868

show subpopulations

Gnomad4 AFR exome

AF:

0.0000385

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000522

Gnomad4 EAS exome

AF:

0.0684

Gnomad4 SAS exome

AF:

0.00177

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000455

Gnomad4 OTH exome

AF:

0.00314

GnomAD4 genome

AF:

0.00228

AC:

244

AN:

107142

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

AN XY:

30332

show subpopulations

Gnomad4 AFR

AF:

0.000102

Gnomad4 AMR

AF:

0.000300

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0672

Gnomad4 SAS

AF:

0.00248

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000135

Gnomad4 OTH

AF:

0.00208

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 12, 2018	Variant summary: WAS c.273+10_273+11dupCC alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0046 in 176885 control chromosomes, predominantly at a frequency of 221 within the East Asian subpopulation in the gnomAD database, including 25 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 62508.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in WAS causing Wiskott-Aldrich Syndrome phenotype (0.0035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.273+10_273+11dupCC in individuals affected with Wiskott-Aldrich Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 30, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2021	In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 30738478) -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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