6-110101779-G-A

Position:

• chr6-110101779-G-A

Variant summary

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

The NM_003931.3(WASF1):​c.1331C>T​(p.Thr444Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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)
• Consequence: WASF1 NM_003931.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.83

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=0.20051631).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WASF1	NM_003931.3	c.1331C>T	p.Thr444Ile	missense_variant	10/11	ENST00000392589.6
WASF1	NM_001024934.2	c.1331C>T	p.Thr444Ile	missense_variant	9/10
WASF1	NM_001024935.2	c.1331C>T	p.Thr444Ile	missense_variant	9/10
WASF1	NM_001024936.2	c.1331C>T	p.Thr444Ile	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WASF1	ENST00000392589.6	c.1331C>T	p.Thr444Ile	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: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 25, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	T;T;T;T;T
Eigen	Benign	-0.044
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	.;.;.;.;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N;N;N;N
MutationTaster	Benign	0.87	D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.26	N;N;N;N;N
REVEL	Benign	0.076
Sift	Benign	0.086	T;T;T;T;T
Sift4G	Benign	0.41	T;T;T;T;T
Polyphen		0.037	B;B;B;B;B
Vest4		0.43
MutPred		0.34		Loss of glycosylation at T444 (P = 0.006);Loss of glycosylation at T444 (P = 0.006);Loss of glycosylation at T444 (P = 0.006);Loss of glycosylation at T444 (P = 0.006);Loss of glycosylation at T444 (P = 0.006);
MVP		0.14
MPC		1.1
ClinPred		0.59	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.062
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr6-110422982;