6-110101735-G-C

Position:

• chr6-110101735-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003931.3(WASF1):​c.1375C>G​(p.Pro459Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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: 1.37

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08636898).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASF1	NM_003931.3	c.1375C>G	p.Pro459Ala	missense_variant	10/11	ENST00000392589.6	NP_003922.1
WASF1	NM_001024934.2	c.1375C>G	p.Pro459Ala	missense_variant	9/10		NP_001020105.1
WASF1	NM_001024935.2	c.1375C>G	p.Pro459Ala	missense_variant	9/10		NP_001020106.1
WASF1	NM_001024936.2	c.1375C>G	p.Pro459Ala	missense_variant	8/9		NP_001020107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASF1	ENST00000392589.6	c.1375C>G	p.Pro459Ala	missense_variant	10/11	5	NM_003931.3	ENSP00000376368	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

May 08, 2024

The WASF1 c.1375C>G variant is predicted to result in the amino acid substitution p.Pro459Ala. To our knowledge, this variant has not been reported in the literature or in a large population database, 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	0.050
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Benign	0.18
DEOGEN2	Benign	0.070	T;T;T;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.77	.;.;.;.;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.086	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Benign	0.050
Sift	Benign	0.51	T;T;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.0010	B;B;B;B;B
Vest4		0.24
MutPred		0.10		Loss of glycosylation at P459 (P = 0.0474);Loss of glycosylation at P459 (P = 0.0474);Loss of glycosylation at P459 (P = 0.0474);Loss of glycosylation at P459 (P = 0.0474);Loss of glycosylation at P459 (P = 0.0474);
MVP		0.068
MPC		0.54
ClinPred		0.13	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr6-110422938;