20-25079460-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G160V) has been classified as Likely benign.

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

Publications

39 publications found

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 Gene-Disease associations (from GenCC):

posterior polymorphous corneal dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
keratoconus 1
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae)
craniofacial anomalies and anterior segment dysgenesis syndrome
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
posterior polymorphous corneal dystrophy 1
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

VSX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 5248.

BS2

High AC in GnomAd4 at 299 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014588.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VSX1	NM_014588.6	MANE Select	c.479G>A	p.Gly160Asp	missense	Exon 2 of 5	NP_055403.2
VSX1	NM_001256272.2		c.479G>A	p.Gly160Asp	missense	Exon 2 of 5	NP_001243201.1	Q9NZR4-8
VSX1	NM_199425.3		c.479G>A	p.Gly160Asp	missense	Exon 2 of 3	NP_955457.1	Q9NZR4-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VSX1	ENST00000376709.9	TSL:1 MANE Select	c.479G>A	p.Gly160Asp	missense	Exon 2 of 5	ENSP00000365899.3	Q9NZR4-1
VSX1	ENST00000429762.7	TSL:1	c.479G>A	p.Gly160Asp	missense	Exon 2 of 5	ENSP00000401690.3	Q9NZR4-8
VSX1	ENST00000376707.4	TSL:1	c.479G>A	p.Gly160Asp	missense	Exon 2 of 3	ENSP00000365897.3	Q9NZR4-2

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

GnomAD2 exomes

AF:

0.00194

AC:

485

AN:

249512

AF XY:

0.00184

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 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

African (AFR)

AF:

0.000239

AC:

AN:

33458

American (AMR)

AF:

0.00116

AC:

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.00414

AC:

108

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000175

AC:

AN:

85858

European-Finnish (FIN)

AF:

0.00249

AC:

133

AN:

53402

Middle Eastern (MID)

AF:

0.000374

AC:

AN:

5350

European-Non Finnish (NFE)

AF:

0.00239

AC:

2652

AN:

1111740

Other (OTH)

AF:

0.00172

AC:

104

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

152

305

457

610

762

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00196

AC:

299

AN:

152220

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

139

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41532

American (AMR)

AF:

0.000327

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00283

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00347

AC:

236

AN:

68020

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000566

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Posterior polymorphous corneal dystrophy (1)

Posterior polymorphous corneal dystrophy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Uncertain

0.10

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.090

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.56

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.2

PhyloP100

1.4

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.61

Sift

Benign

0.31

Sift4G

Benign

0.44

Polyphen

0.080

Vest4

0.59

MVP

0.87

MPC

0.14

ClinPred

0.011

GERP RS

3.7

Varity_R

0.15

gMVP

0.21

Mutation Taster

=3/97

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over