20-25079464-A-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3BP6_ModerateBS2

The NM_014588.6(VSX1):c.475T>A(p.Leu159Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000088 in 1,612,832 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

VSX1
NM_014588.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 1.54

Publications

24 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: G2P, Laboratory for Molecular Medicine, 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: Likely_benign. The variant received -5 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.819

BP6

Variant 20-25079464-A-T is Benign according to our data. Variant chr20-25079464-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 5249.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 138 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSX1	NM_014588.6 link	c.475T>A	p.Leu159Met	missense_variant	Exon 2 of 5	ENST00000376709.9	NP_055403.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VSX1	ENST00000376709.9 link	c.475T>A	p.Leu159Met	missense_variant	Exon 2 of 5	1	NM_014588.6	ENSP00000365899.3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152114

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000481

AC:

AN:

249630

AF XY:

0.0000593

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000945

AC:

138

AN:

1460718

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

726532

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

85880

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5416

European-Non Finnish (NFE)

AF:

0.000123

AC:

137

AN:

1111764

Other (OTH)

AF:

0.0000166

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000434

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Keratoconus 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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Uncertain

0.040

CADD

Benign

6.4

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;.;T;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.78

LIST_S2

Benign

0.22

T;T;T;T

M_CAP

Benign

0.074

MetaRNN

Pathogenic

0.82

D;D;D;D

MetaSVM

Uncertain

-0.013

MutationAssessor

Benign

1.5

L;L;L;L

PhyloP100

1.5

PrimateAI

Benign

0.35

PROVEAN

Benign

0.30

N;N;N;N

Sift

Benign

0.16

T;T;T;T

Sift4G

Benign

0.28

T;T;T;T

Vest4

0.61

ClinPred

0.11

GERP RS

1.6

Varity_R

0.080

gMVP

0.18

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over