chr6-110101674-A-G

Position:

• chr6-110101674-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003931.3(WASF1):​c.1436T>C​(p.Ile479Thr) 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 1,461,806 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: 2.06

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060835004).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WASF1	NM_003931.3	c.1436T>C	p.Ile479Thr	missense_variant	10/11	ENST00000392589.6
WASF1	NM_001024934.2	c.1436T>C	p.Ile479Thr	missense_variant	9/10
WASF1	NM_001024935.2	c.1436T>C	p.Ile479Thr	missense_variant	9/10
WASF1	NM_001024936.2	c.1436T>C	p.Ile479Thr	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WASF1	ENST00000392589.6	c.1436T>C	p.Ile479Thr	missense_variant	10/11	5	NM_003931.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461806 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

Gnomad4 AFR exome AF: 0.0000299

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: 8.99e-7

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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 15, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with WASF1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 479 of the WASF1 protein (p.Ile479Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Benign	0.78
DEOGEN2	Benign	0.072	T;T;T;T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.68	.;.;.;.;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.061	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.030	N;N;N;N;N
REVEL	Benign	0.036
Sift	Benign	0.51	T;T;T;T;T
Sift4G	Benign	0.42	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.064
MutPred		0.19		Gain of glycosylation at I479 (P = 0.0042);Gain of glycosylation at I479 (P = 0.0042);Gain of glycosylation at I479 (P = 0.0042);Gain of glycosylation at I479 (P = 0.0042);Gain of glycosylation at I479 (P = 0.0042);
MVP		0.043
MPC		0.71
ClinPred		0.15	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs1562159641; hg19: chr6-110422877;