6-110101630-T-C

Position:

• chr6-110101630-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003931.3(WASF1):​c.1480A>G​(p.Ile494Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WASF1 NM_003931.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.72

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASF1	NM_003931.3	c.1480A>G	p.Ile494Val	missense_variant	10/11	ENST00000392589.6	NP_003922.1
WASF1	NM_001024934.2	c.1480A>G	p.Ile494Val	missense_variant	9/10		NP_001020105.1
WASF1	NM_001024935.2	c.1480A>G	p.Ile494Val	missense_variant	9/10		NP_001020106.1
WASF1	NM_001024936.2	c.1480A>G	p.Ile494Val	missense_variant	8/9		NP_001020107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASF1	ENST00000392589.6	c.1480A>G	p.Ile494Val	missense_variant	10/11	5	NM_003931.3	ENSP00000376368.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

WASF1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2024

The WASF1 c.1480A>G variant is predicted to result in the amino acid substitution p.Ile494Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.070	T;T;T;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.63	.;.;.;.;T
M_CAP	Benign	0.0094	T
MetaRNN	Uncertain	0.44	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.24	N;N;N;N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.13	N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.16	T;T;T;T;T
Sift4G	Benign	0.65	T;T;T;T;T
Polyphen		0.90	P;P;P;P;P
Vest4		0.55
MutPred		0.37		Gain of MoRF binding (P = 0.1311);Gain of MoRF binding (P = 0.1311);Gain of MoRF binding (P = 0.1311);Gain of MoRF binding (P = 0.1311);Gain of MoRF binding (P = 0.1311);
MVP		0.17
MPC		0.74
ClinPred		0.49	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.048
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-110422833;