rs200543049

Positions:

• chrX-48689450-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000377.3(WAS):​c.1453+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,188,626 control chromosomes in the GnomAD database, including 1 homozygotes. There are 522 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., 28 hem., cov: 23)
  • Exomes 𝑓: 0.0015 (0 hom. 494 hem.)
• Consequence: WAS NM_000377.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.332

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-48689450-C-T is Benign according to our data. Variant chrX-48689450-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48689450-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00116 (129/110937) while in subpopulation NFE AF= 0.00193 (102/52929). AF 95% confidence interval is 0.00162. There are 1 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 28 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WAS	NM_000377.3	c.1453+16C>T		intron_variant		ENST00000376701.5	NP_000368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WAS	ENST00000376701.5	c.1453+16C>T		intron_variant		1	NM_000377.3	ENSP00000365891.4

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 129 AN: 110882 Hom.: 1 Cov.: 23 AF XY: 0.000846 AC XY: 28 AN XY: 33092

Gnomad AFR AF: 0.000197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00106

Gnomad ASJ AF: 0.000757

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000380

Gnomad FIN AF: 0.000340

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00145 AC: 230 AN: 158738 Hom.: 0 AF XY: 0.00155 AC XY: 77 AN XY: 49748

Gnomad AFR exome AF: 0.000357

Gnomad AMR exome AF: 0.00100

Gnomad ASJ exome AF: 0.00144

Gnomad EAS exome AF: 0.00113

Gnomad SAS exome AF: 0.000793

Gnomad FIN exome AF: 0.0000700

Gnomad NFE exome AF: 0.00220

Gnomad OTH exome AF: 0.00297

GnomAD4 exome AF: 0.00151 AC: 1622 AN: 1077689 Hom.: 0 Cov.: 30 AF XY: 0.00143 AC XY: 494 AN XY: 345833

Gnomad4 AFR exome AF: 0.0000766

Gnomad4 AMR exome AF: 0.000893

Gnomad4 ASJ exome AF: 0.00105

Gnomad4 EAS exome AF: 0.000402

Gnomad4 SAS exome AF: 0.000481

Gnomad4 FIN exome AF: 0.000176

Gnomad4 NFE exome AF: 0.00169

Gnomad4 OTH exome AF: 0.00201

GnomAD4 genome AF: 0.00116 AC: 129 AN: 110937 Hom.: 1 Cov.: 23 AF XY: 0.000844 AC XY: 28 AN XY: 33157

Gnomad4 AFR AF: 0.000197

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000757

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000381

Gnomad4 FIN AF: 0.000340

Gnomad4 NFE AF: 0.00193

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00142 Hom.: 13

Bravo AF: 0.00116

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wiskott-Aldrich syndrome;C1839163:Thrombocytopenia 1;C1845987:X-linked severe congenital neutropenia Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 02, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Wiskott-Aldrich syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.8
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs200543049; hg19: chrX-48547839;