20-25079460-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_014588.6(VSX1):c.479G>A(p.Gly160Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,612,800 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 10 hom. )

Consequence

VSX1
NM_014588.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.39

Variant links:

Genes affected

VSX1 (HGNC:12723): (visual system homeobox 1) The protein encoded by this gene contains a paired-like homeodomain and binds to the core of the locus control region of the red/green visual pigment gene cluster. The encoded protein may regulate expression of the cone opsin genes early in development. Mutations in this gene can cause posterior polymorphous corneal dystrophy and keratoconus. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

VSX1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01545766).

BP6

Variant 20-25079460-C-T is Benign according to our data. Variant chr20-25079460-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5248.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}. Variant chr20-25079460-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 299 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSX1	NM_014588.6 link	c.479G>A	p.Gly160Asp	missense_variant	Exon 2 of 5	ENST00000376709.9	NP_055403.2	Q9NZR4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VSX1	ENST00000376709.9 link	c.479G>A	p.Gly160Asp	missense_variant	Exon 2 of 5	1	NM_014588.6	ENSP00000365899.3		Q9NZR4-1

Frequencies

GnomAD3 genomes

AF:

0.00197

AC:

299

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00347

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.00194

AC:

485

AN:

249512

Hom.:

AF XY:

0.00184

AC XY:

248

AN XY:

134874

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00399

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000993

Gnomad FIN exome

AF:

0.00202

Gnomad NFE exome

AF:

0.00308

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00210

AC:

3074

AN:

1460580

Hom.:

Cov.:

AF XY:

0.00213

AC XY:

1544

AN XY:

726500

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.00414

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000175

Gnomad4 FIN exome

AF:

0.00249

Gnomad4 NFE exome

AF:

0.00239

Gnomad4 OTH exome

AF:

0.00172

GnomAD4 genome

AF:

0.00196

AC:

299

AN:

152220

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

139

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00283

Gnomad4 NFE

AF:

0.00347

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000562

Hom.:

Bravo

AF:

0.00154

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00186

AC:

226

EpiCase

AF:

0.00240

EpiControl

AF:

0.00220

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Please see the NVA form. Variant not conserved. VUS4 based on nonsegregation, frequency, and lack of conservation. Gene is associated with adult-onset keratocounus with reduced penetrance. Data suggests that earlier onset of corneal dystrophy is possible when 2 variants are present, but additional data is needed to understand whether this is true. -

Posterior polymorphous corneal dystrophy 1

Uncertain:1

Jan 01, 2011

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Posterior polymorphous corneal dystrophy

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Uncertain

0.10

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

.;.;T;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.090

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.56

T;T;T;T

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.2

M;M;M;M

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.0

N;N;N;D

REVEL

Uncertain

0.61

Sift

Benign

0.31

T;T;T;T

Sift4G

Benign

0.44

T;T;T;T

Polyphen

0.080

B;P;B;B

Vest4

0.59

MVP

0.87

MPC

0.14

ClinPred

0.011

GERP RS

3.7

Varity_R

0.15

gMVP

0.21

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

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