chr3-37994412-A-C

Position:

• chr3-37994412-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015873.4(VILL):​c.287A>C​(p.Glu96Ala) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VILL NM_015873.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.00

Genes affected

VILL (HGNC:30906): (villin like) The protein encoded by this gene belongs to the villin/gelsolin family. It contains 6 gelsolin-like repeats and a headpiece domain. It may play a role in actin-bundling. [provided by RefSeq, Jul 2008]

VILL (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VILL	NM_015873.4	c.287A>C	p.Glu96Ala	missense_variant	4/20	ENST00000383759.7	NP_056957.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VILL	ENST00000383759.7	c.287A>C	p.Glu96Ala	missense_variant	4/20	5	NM_015873.4	ENSP00000373266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The c.287A>C (p.E96A) alteration is located in exon 3 (coding exon 3) of the VILL gene. This alteration results from a A to C substitution at nucleotide position 287, causing the glutamic acid (E) at amino acid position 96 to be replaced by an alanine (A). 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	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.;T;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;.
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.026	D
MutationAssessor	Pathogenic	3.8	H;.;.;H
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.6	D;D;D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.89
MutPred		0.77		Loss of disorder (P = 0.0695);Loss of disorder (P = 0.0695);Loss of disorder (P = 0.0695);Loss of disorder (P = 0.0695);
MVP		0.64
MPC		0.80
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.79
gMVP		0.87

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: chr3-38035903;