Variant 3-37993959-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_015873.4(VILL):c.122A>G(p.Tyr41Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

VILL
NM_015873.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.08

Variant links:

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 links:

VILL (HGNC:):

VILL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VILL	NM_015873.4 linkuse as main transcript	c.122A>G	p.Tyr41Cys	missense_variant	3/20	ENST00000383759.7	NP_056957.3	O15195-1
VILL	NM_001385038.1 linkuse as main transcript	c.122A>G	p.Tyr41Cys	missense_variant	4/21		NP_001371967.1
VILL	NM_001385039.1 linkuse as main transcript	c.122A>G	p.Tyr41Cys	missense_variant	3/20		NP_001371968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
VILL	ENST00000383759.7 linkuse as main transcript	c.122A>G	p.Tyr41Cys	missense_variant	3/20	5	NM_015873.4	ENSP00000373266.2	O15195-1
VILL	ENST00000283713.10 linkuse as main transcript	c.122A>G	p.Tyr41Cys	missense_variant	3/20	1		ENSP00000283713.6	O15195-1
VILL	ENST00000492491.6 linkuse as main transcript	c.122A>G	p.Tyr41Cys	missense_variant	3/6	5		ENSP00000427355.1	E9PFV5
VILL	ENST00000460040.1 linkuse as main transcript	n.402A>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251482

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000439

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727246

show subpopulations

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:

0.0000288

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2022

The c.122A>G (p.Y41C) alteration is located in exon 2 (coding exon 2) of the VILL gene. This alteration results from a A to G substitution at nucleotide position 122, causing the tyrosine (Y) at amino acid position 41 to be replaced by a cysteine (C). 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

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

T;.;T;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D;D;.

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Uncertain

0.31

MutationAssessor

Pathogenic

3.8

H;.;.;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-7.8

D;D;D;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;D

Vest4

0.92

MutPred

0.78

Loss of phosphorylation at Y41 (P = 0.0362);Loss of phosphorylation at Y41 (P = 0.0362);Loss of phosphorylation at Y41 (P = 0.0362);Loss of phosphorylation at Y41 (P = 0.0362);

MVP

0.87

MPC

0.88

ClinPred

1.0

GERP RS

4.2

Varity_R

0.94

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over