6-110101630-T-C

Position:

• chr6-110101630-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I494MP?) has been classified as Pathogenic.

• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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	UniProt
WASF1	NM_003931.3	c.1480A>G	p.Ile494Val	missense_variant	10/11	ENST00000392589.6
WASF1	NM_001024934.2	c.1480A>G	p.Ile494Val	missense_variant	9/10
WASF1	NM_001024935.2	c.1480A>G	p.Ile494Val	missense_variant	9/10
WASF1	NM_001024936.2	c.1480A>G	p.Ile494Val	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WASF1	ENST00000392589.6	c.1480A>G	p.Ile494Val	missense_variant	10/11	5	NM_003931.3	P1

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
MutationTaster	Benign	1.0	D;D;D;D;D
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;