X-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+4_273+5insCC variant causes a splice 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_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]

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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 rank MANE Protein UniProt
WASNM_000377.3 linkc.273+10_273+11dupCC intron_variant Intron 2 of 11 ENST00000376701.5 NP_000368.1 P42768A0A024QYX8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
WASENST00000376701.5 linkc.273+4_273+5insCC splice_region_variant, intron_variant Intron 2 of 11 1 NM_000377.3 ENSP00000365891.4 P42768

Frequencies

GnomAD3 genomes
AF:
0.00231
AC:
247
AN:
107101
Hom.:
5
Cov.:
21
AF XY:
0.00258
AC XY:
78
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.:
29
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.:
60
Cov.:
32
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.:
5
Cov.:
21
AF XY:
0.00251
AC XY:
76
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
-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 12, 2018
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Oct 30, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:2
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 13, 2021
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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.

Other links and lift over

dbSNP: rs58371799; hg19: chrX-48542816; API