chr6-110101851-A-C

Position:

• chr6-110101851-A-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.1259T>G​(p.Val420Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WASF1 NM_003931.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.70

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=0.07918212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WASF1	NM_003931.3	c.1259T>G	p.Val420Gly	missense_variant	10/11	ENST00000392589.6
WASF1	NM_001024934.2	c.1259T>G	p.Val420Gly	missense_variant	9/10
WASF1	NM_001024935.2	c.1259T>G	p.Val420Gly	missense_variant	9/10
WASF1	NM_001024936.2	c.1259T>G	p.Val420Gly	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WASF1	ENST00000392589.6	c.1259T>G	p.Val420Gly	missense_variant	10/11	5	NM_003931.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461640 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2023

The c.1259T>G (p.V420G) alteration is located in exon 10 (coding exon 7) of the WASF1 gene. This alteration results from a T to G substitution at nucleotide position 1259, causing the valine (V) at amino acid position 420 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.071	T;T;T;T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.56	.;.;.;.;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.079	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.15	N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.52	T;T;T;T;T
Sift4G	Benign	0.40	T;T;T;T;T
Polyphen		0.018	B;B;B;B;B
Vest4		0.37
MutPred		0.27		Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);
MVP		0.23
MPC		0.90
ClinPred		0.15	T
GERP RS		3.2
Varity_R		0.056
gMVP		0.17

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: chr6-110423054;