6-110101791-G-A

Position:

• chr6-110101791-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_003931.3(WASF1):​c.1319C>T​(p.Ser440Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WASF1 NM_003931.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.14

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-110101791-G-A is Pathogenic according to our data. Variant chr6-110101791-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1314809.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21852016). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASF1	NM_003931.3	c.1319C>T	p.Ser440Leu	missense_variant	10/11	ENST00000392589.6	NP_003922.1
WASF1	NM_001024934.2	c.1319C>T	p.Ser440Leu	missense_variant	9/10		NP_001020105.1
WASF1	NM_001024935.2	c.1319C>T	p.Ser440Leu	missense_variant	9/10		NP_001020106.1
WASF1	NM_001024936.2	c.1319C>T	p.Ser440Leu	missense_variant	8/9		NP_001020107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASF1	ENST00000392589.6	c.1319C>T	p.Ser440Leu	missense_variant	10/11	5	NM_003931.3	ENSP00000376368.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 01, 2023

Not observed 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	0.10
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T;T;T;T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;.;.;.;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N;N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.012	D;D;D;D;D
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		0.084	B;B;B;B;B
Vest4		0.44
MutPred		0.27		Loss of glycosylation at S440 (P = 0.0046);Loss of glycosylation at S440 (P = 0.0046);Loss of glycosylation at S440 (P = 0.0046);Loss of glycosylation at S440 (P = 0.0046);Loss of glycosylation at S440 (P = 0.0046);
MVP		0.093
MPC		1.0
ClinPred		0.77	D
GERP RS		5.9
Varity_R		0.11
gMVP		0.37

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: chr6-110422994;