chr6-110101628-G-CCTGGC

Position:

• chr6-110101628-G-CCTGGC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_003931.3(WASF1):​c.1482delinsGCCAGG​(p.Ile494MetfsTer23) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WASF1 NM_003931.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 5.21

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 Likely_pathogenic. Variant got 7 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. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-110101628-G-CCTGGC is Pathogenic according to our data. Variant chr6-110101628-G-CCTGGC is described in ClinVar as [Pathogenic]. Clinvar id is 561982.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASF1	NM_003931.3	c.1482delinsGCCAGG	p.Ile494MetfsTer23	frameshift_variant	10/11	ENST00000392589.6	NP_003922.1
WASF1	NM_001024934.2	c.1482delinsGCCAGG	p.Ile494MetfsTer23	frameshift_variant	9/10		NP_001020105.1
WASF1	NM_001024935.2	c.1482delinsGCCAGG	p.Ile494MetfsTer23	frameshift_variant	9/10		NP_001020106.1
WASF1	NM_001024936.2	c.1482delinsGCCAGG	p.Ile494MetfsTer23	frameshift_variant	8/9		NP_001020107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASF1	ENST00000392589.6	c.1482delinsGCCAGG	p.Ile494MetfsTer23	frameshift_variant	10/11	5	NM_003931.3	ENSP00000376368	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Neurodevelopmental disorder with absent language and variable seizures Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 20, 2019

- -

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1562159599; hg19: chr6-110422831;