rs2737799

Positions:

• chrX-48688723-T-C

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.995T>C​(p.Val332Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00549 in 1,176,011 control chromosomes in the GnomAD database, including 17 homozygotes. There are 2,014 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (2 hom., 132 hem., cov: 22)
  • Exomes 𝑓: 0.0055 (15 hom. 1882 hem.)
• Consequence: WAS NM_000377.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:8 O:1
• Conservation: PhyloP100: -0.0120

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 (MetaRNN=0.009927154).
• BP6: Variant X-48688723-T-C is Benign according to our data. Variant chrX-48688723-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 135410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48688723-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00492 (536/108981) while in subpopulation AMR AF= 0.00788 (82/10404). AF 95% confidence interval is 0.00651. There are 2 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WAS	NM_000377.3	c.995T>C	p.Val332Ala	missense_variant	10/12	ENST00000376701.5	NP_000368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WAS	ENST00000376701.5	c.995T>C	p.Val332Ala	missense_variant	10/12	1	NM_000377.3	ENSP00000365891.4

Frequencies

GnomAD3 genomes AF: 0.00492 AC: 536 AN: 108934 Hom.: 2 Cov.: 22 AF XY: 0.00417 AC XY: 131 AN XY: 31422

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00789

Gnomad ASJ AF: 0.00539

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00163

Gnomad FIN AF: 0.00713

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00669

Gnomad OTH AF: 0.00682

GnomAD3 exomes AF: 0.00479 AC: 697 AN: 145484 Hom.: 1 AF XY: 0.00450 AC XY: 209 AN XY: 46480

Gnomad AFR exome AF: 0.000633

Gnomad AMR exome AF: 0.00554

Gnomad ASJ exome AF: 0.00311

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00135

Gnomad FIN exome AF: 0.00781

Gnomad NFE exome AF: 0.00624

Gnomad OTH exome AF: 0.00695

GnomAD4 exome AF: 0.00554 AC: 5916 AN: 1067030 Hom.: 15 Cov.: 33 AF XY: 0.00547 AC XY: 1882 AN XY: 343934

Gnomad4 AFR exome AF: 0.00129

Gnomad4 AMR exome AF: 0.00604

Gnomad4 ASJ exome AF: 0.00553

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.00785

Gnomad4 NFE exome AF: 0.00590

Gnomad4 OTH exome AF: 0.00624

GnomAD4 genome AF: 0.00492 AC: 536 AN: 108981 Hom.: 2 Cov.: 22 AF XY: 0.00419 AC XY: 132 AN XY: 31479

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00788

Gnomad4 ASJ AF: 0.00539

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00204

Gnomad4 FIN AF: 0.00713

Gnomad4 NFE AF: 0.00669

Gnomad4 OTH AF: 0.00673

Alfa AF: 0.00645 Hom.: 277

Bravo AF: 0.00466

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00727 AC: 21

ESP6500AA AF: 0.000266 AC: 1

ESP6500EA AF: 0.00467 AC: 31

ExAC AF: 0.00432 AC: 519

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 11, 2019	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2021	This variant is associated with the following publications: (PMID: 27153395, 17400488, 22995991, 24728327, 24369837, 23689198) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 17, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Wiskott-Aldrich syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Uncertain significance, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.0099	T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.26
Sift	Benign	0.49	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.027
MVP		0.78
MPC		0.70
ClinPred		0.0013	T
GERP RS		1.9
Varity_R		0.061
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2737799; hg19: chrX-48547112;