rs145040665

chrX-48686113-C-AchrX-48686113-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000377.3(WAS):c.538C>A(p.His180Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,210,927 control chromosomes in the GnomAD database, including 1 homozygotes. There are 546 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H180H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., 36 hem., cov: 23)
  • Exomes 𝑓: 0.0014 (1 hom. 510 hem.)
• Consequence: WAS NM_000377.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7 O:1
• Conservation: PhyloP100: 1.44

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012371749).
• BP6: Variant X-48686113-C-A is Benign according to our data. Variant chrX-48686113-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36912.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=4, Uncertain_significance=1, Benign=2}. Variant chrX-48686113-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00103 (116/112767) while in subpopulation NFE AF= 0.0018 (96/53303). AF 95% confidence interval is 0.00151. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 36 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WAS	NM_000377.3	c.538C>A	p.His180Asn	missense_variant	6/12	ENST00000376701.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WAS	ENST00000376701.5	c.538C>A	p.His180Asn	missense_variant	6/12	1	NM_000377.3	P2

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 116 AN: 112713 Hom.: 0 Cov.: 23 AF XY: 0.00103 AC XY: 36 AN XY: 34855

Gnomad AFR AF: 0.000129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000281

Gnomad ASJ AF: 0.00451

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00180

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00101 AC: 186 AN: 183265 Hom.: 1 AF XY: 0.00103 AC XY: 70 AN XY: 67741

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000255

Gnomad ASJ exome AF: 0.00548

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.00137 AC: 1506 AN: 1098160 Hom.: 1 Cov.: 33 AF XY: 0.00140 AC XY: 510 AN XY: 363518

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.000426

Gnomad4 ASJ exome AF: 0.00495

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00153

Gnomad4 OTH exome AF: 0.00158

GnomAD4 genome AF: 0.00103 AC: 116 AN: 112767 Hom.: 0 Cov.: 23 AF XY: 0.00103 AC XY: 36 AN XY: 34919

Gnomad4 AFR AF: 0.000129

Gnomad4 AMR AF: 0.000281

Gnomad4 ASJ AF: 0.00451

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000161

Gnomad4 NFE AF: 0.00180

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00169 Hom.: 69

Bravo AF: 0.00110

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00138 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00208 AC: 14

ExAC AF: 0.000840 AC: 102

EpiCase AF: 0.00338

EpiControl AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 15, 2017	- -

not specified Benign:2 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 19, 2017	- -

Thrombocytopenia 1 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 02, 2015

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

WAS-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2020

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	15
Dann	Benign	0.95
DEOGEN2	Benign	0.0077	T;T
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.61	T;T
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Pathogenic	0.86	D
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.16	N;N
REVEL	Uncertain	0.41
Sift	Benign	0.48	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.48	.;P
Vest4		0.088
MVP		0.84
MPC		0.77
ClinPred		0.0080	T
GERP RS		4.3
Varity_R		0.15
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs145040665; hg19: chrX-48544502;