rs148800063

chrX-48683943-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000377.3(WAS):c.90C>T(p.His30=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000968 in 1,209,192 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 388 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 0.00059 (0 hom., 16 hem., cov: 22)
  • Exomes 𝑓: 0.0010 (0 hom. 372 hem.)
• Consequence: WAS NM_000377.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.85

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant X-48683943-C-T is Benign according to our data. Variant chrX-48683943-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 458506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48683943-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000586 (65/110945) while in subpopulation SAS AF= 0.00114 (3/2639). AF 95% confidence interval is 0.000854. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WAS	NM_000377.3	c.90C>T	p.His30=	synonymous_variant	1/12	ENST00000376701.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WAS	ENST00000376701.5	c.90C>T	p.His30=	synonymous_variant	1/12	1	NM_000377.3	P2

Frequencies

GnomAD3 genomes AF: 0.000586 AC: 65 AN: 110945 Hom.: 0 Cov.: 22 AF XY: 0.000483 AC XY: 16 AN XY: 33103

Gnomad AFR AF: 0.000131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000956

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00114

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00108

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000714 AC: 131 AN: 183418 Hom.: 0 AF XY: 0.000855 AC XY: 58 AN XY: 67856

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000891

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.000883

GnomAD4 exome AF: 0.00101 AC: 1106 AN: 1098247 Hom.: 0 Cov.: 31 AF XY: 0.00102 AC XY: 372 AN XY: 363603

Gnomad4 AFR exome AF: 0.000265

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.000103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000572

Gnomad4 FIN exome AF: 0.000123

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.000824

GnomAD4 genome AF: 0.000586 AC: 65 AN: 110945 Hom.: 0 Cov.: 22 AF XY: 0.000483 AC XY: 16 AN XY: 33103

Gnomad4 AFR AF: 0.000131

Gnomad4 AMR AF: 0.0000956

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00114

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00108

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000582 Hom.: 5

Bravo AF: 0.000567

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 26, 2018

- -

WAS-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	2.4
Dann	Benign	0.93

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: rs148800063; hg19: chrX-48542332;