X-48684427-A-ACC

Variant names:

• chrX-48684427-A-ACC
• rs58371799
• NM_000377.3:c.273+10_273+11dupCC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0540

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]

ACMG classification

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
WAS	NM_000377.3	c.273+10_273+11dupCC		intron_variant	Intron 2 of 11	ENST00000376701.5	NP_000368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WAS	ENST00000376701.5	c.273+4_273+5insCC		splice_region_variant, intron_variant	Intron 2 of 11	1	NM_000377.3	ENSP00000365891.4

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 247 AN: 107101 Hom.: 5 Cov.: 21 AF XY: 0.00258 AC XY: 78 AN XY: 30281

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

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

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

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

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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. -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

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) -

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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

- -

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs58371799; hg19: chrX-48542816;