6-110101644-G-C

Position:

• chr6-110101644-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_003931.3(WASF1):​c.1466C>G​(p.Ser489Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WASF1 NM_003931.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.47

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 8 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 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-110101644-G-C is Pathogenic according to our data. Variant chr6-110101644-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1342385.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WASF1	NM_003931.3	c.1466C>G	p.Ser489Ter	stop_gained	10/11	ENST00000392589.6
WASF1	NM_001024934.2	c.1466C>G	p.Ser489Ter	stop_gained	9/10
WASF1	NM_001024935.2	c.1466C>G	p.Ser489Ter	stop_gained	9/10
WASF1	NM_001024936.2	c.1466C>G	p.Ser489Ter	stop_gained	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WASF1	ENST00000392589.6	c.1466C>G	p.Ser489Ter	stop_gained	10/11	5	NM_003931.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with absent language and variable seizures Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Mar 05, 2021

The de novo c.1466C>G (p.Ser489Ter) variant identified in the WASF1 gene is a single nucleotide variant leading to the premature termination of the protein at amino acid 489/560 (exon 9/10). This variant is absent from gnomAD(v3.1) suggesting it is not a common benign variant in the populations represented in that database. This variant is absent from ClinVar, and to our current knowledge has not been reported in the literature, although several nonsense and frameshift variants downstream of the one identified here have been reported in affected individuals [PMID:29961568]. Given its deleterious nature, absence in population databases, and presence de novo, the c.1466C>G (p.Ser489Ter) variant identified in the WASF1 gene is reported as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.63
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-110422847;