chrX-48684427-A-AC

Position:

• chrX-48684427-A-AC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000376701.5(WAS):​c.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 0.0163 in 1,193,093 control chromosomes in the GnomAD database, including 123 homozygotes. There are 6,039 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (25 hom., 492 hem., cov: 21)
  • Exomes 𝑓: 0.016 (98 hom. 5547 hem.)
• Consequence: WAS ENST00000376701.5 splice_donor_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• 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-AC is Benign according to our data. Variant chrX-48684427-A-AC is described in ClinVar as [Likely_benign]. Clinvar id is 255964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0192 (2057/107140) while in subpopulation AFR AF= 0.0312 (914/29267). AF 95% confidence interval is 0.0296. There are 25 homozygotes in gnomad4. There are 492 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WAS	NM_000377.3	c.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	c.273+11dup		splice_donor_region_variant, intron_variant		1	NM_000377.3	ENSP00000365891	P2

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2046 AN: 107099 Hom.: 23 Cov.: 21 AF XY: 0.0162 AC XY: 491 AN XY: 30277

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.0166

Gnomad AMR AF: 0.00991

Gnomad ASJ AF: 0.0128

Gnomad EAS AF: 0.00150

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.00980

Gnomad MID AF: 0.0172

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.0224

GnomAD3 exomes AF: 0.0137 AC: 2214 AN: 161608 Hom.: 14 AF XY: 0.0123 AC XY: 638 AN XY: 51748

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.00776

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.00226

Gnomad SAS exome AF: 0.0129

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0160 AC: 17385 AN: 1085953 Hom.: 98 Cov.: 32 AF XY: 0.0157 AC XY: 5547 AN XY: 353855

Gnomad4 AFR exome AF: 0.0323

Gnomad4 AMR exome AF: 0.00793

Gnomad4 ASJ exome AF: 0.0159

Gnomad4 EAS exome AF: 0.00260

Gnomad4 SAS exome AF: 0.0139

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.0167

Gnomad4 OTH exome AF: 0.0158

GnomAD4 genome AF: 0.0192 AC: 2057 AN: 107140 Hom.: 25 Cov.: 21 AF XY: 0.0162 AC XY: 492 AN XY: 30328

Gnomad4 AFR AF: 0.0312

Gnomad4 AMR AF: 0.00990

Gnomad4 ASJ AF: 0.0128

Gnomad4 EAS AF: 0.00151

Gnomad4 SAS AF: 0.0186

Gnomad4 FIN AF: 0.00980

Gnomad4 NFE AF: 0.0165

Gnomad4 OTH AF: 0.0277

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	WAS: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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;