6-110101594-G-A

Position:

• chr6-110101594-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_003931.3(WASF1):​c.1516C>T​(p.Arg506*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WASF1 NM_003931.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.83

Genes affected

WASF1 (HGNC:12732): (WASP family member 1) The protein encoded by this gene, a member of the Wiskott-Aldrich syndrome protein (WASP)-family, plays a critical role downstream of Rac, a Rho-family small GTPase, in regulating the actin cytoskeleton required for membrane ruffling. It has been shown to associate with an actin nucleation core Arp2/3 complex while enhancing actin polymerization in vitro. Wiskott-Aldrich syndrome is a disease of the immune system, likely due to defects in regulation of actin cytoskeleton. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0976 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-110101594-G-A is Pathogenic according to our data. Variant chr6-110101594-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 561980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-110101594-G-A is described in Lovd as [Pathogenic]. Variant chr6-110101594-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASF1	NM_003931.3	c.1516C>T	p.Arg506*	stop_gained	10/11	ENST00000392589.6	NP_003922.1
WASF1	NM_001024934.2	c.1516C>T	p.Arg506*	stop_gained	9/10		NP_001020105.1
WASF1	NM_001024935.2	c.1516C>T	p.Arg506*	stop_gained	9/10		NP_001020106.1
WASF1	NM_001024936.2	c.1516C>T	p.Arg506*	stop_gained	8/9		NP_001020107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASF1	ENST00000392589.6	c.1516C>T	p.Arg506*	stop_gained	10/11	5	NM_003931.3	ENSP00000376368.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with absent language and variable seizures Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Heidelberg University	Jun 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Jan 23, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 20, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Rehabilitation, Children’s Hospital of Chongqing Medical University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 26, 2023	Variant summary: WASF1 c.1516C>T (p.Arg506X) results in a premature termination codon that has been reported to result in a truncation of the encoded protein (Ito_2018) and predicted to disrupt the C-terminal actin binding WCA domain. The variant was absent in 247760 control chromosomes. c.1516C>T has been reported in the literature as a recurrent de-novo variant in individuals affected with features of Neurodevelopmental Disorder With Absent Language And Variable Seizures (example, Ito_2018, Srivastava_2021, Shimojima_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function reporting a defect in actin remodeling (Ito_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 10, 2024	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 10 of 11). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Two other variants predicted to cause a truncated protein have been reported as pathogenic (ClinVar, PMID: 29961568). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in patients with intellectual disability (ClinVar, PMID: 29961568). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1001 - Strong functional evidence supporting abnormal protein function. Functional studies using fibroblast cells from two affected individuals showed a truncated WASF1 and a defect in actin remodeling (PMID: 29961568). (P) 1204 - Variant shown to be de novo in proband (parental status not tested but assumed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	WASF1: PS2:Very Strong, PM2, PS4:Moderate, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2022	Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is not a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29961568, 34845217, 34356165) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Intellectual disability Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.92
GERP RS		5.9

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: rs1562159562; hg19: chr6-110422797; COSMIC: COSV100846939;