rs369865672

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_014588.6(VSX1):c.173C>T(p.Pro58Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00102 in 1,530,740 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P58P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 2 hom. )

Consequence

VSX1
NM_014588.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 3.61

Publications

3 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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09894732).

BP6

Variant 20-25081924-G-A is Benign according to our data. Variant chr20-25081924-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 337970.

BS2

High AC in GnomAd4 at 133 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
VSX1	NM_014588.6	MANE Select	c.173C>T	p.Pro58Leu	missense	Exon 1 of 5	NP_055403.2
VSX1	NM_001256272.2		c.173C>T	p.Pro58Leu	missense	Exon 1 of 5	NP_001243201.1
VSX1	NM_199425.3		c.173C>T	p.Pro58Leu	missense	Exon 1 of 3	NP_955457.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VSX1	ENST00000376709.9	TSL:1 MANE Select	c.173C>T	p.Pro58Leu	missense	Exon 1 of 5	ENSP00000365899.3
VSX1	ENST00000429762.7	TSL:1	c.173C>T	p.Pro58Leu	missense	Exon 1 of 5	ENSP00000401690.3
VSX1	ENST00000376707.4	TSL:1	c.173C>T	p.Pro58Leu	missense	Exon 1 of 3	ENSP00000365897.3

Frequencies

GnomAD3 genomes

AF:

0.000874

AC:

133

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000884

AC:

112

AN:

126708

AF XY:

0.000909

show subpopulations

Gnomad AFR exome

AF:

0.000168

Gnomad AMR exome

AF:

0.00132

Gnomad ASJ exome

AF:

0.000755

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00141

Gnomad OTH exome

AF:

0.00127

GnomAD4 exome

AF:

0.00104

AC:

1429

AN:

1378478

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

691

AN XY:

679850

show subpopulations

African (AFR)

AF:

0.000256

AC:

AN:

31296

American (AMR)

AF:

0.00127

AC:

AN:

35494

Ashkenazi Jewish (ASJ)

AF:

0.000520

AC:

AN:

25010

East Asian (EAS)

AF:

0.00

AC:

AN:

35634

South Asian (SAS)

AF:

0.000127

AC:

AN:

78952

European-Finnish (FIN)

AF:

0.000539

AC:

AN:

33392

Middle Eastern (MID)

AF:

0.00511

AC:

AN:

4110

European-Non Finnish (NFE)

AF:

0.00115

AC:

1243

AN:

1077044

Other (OTH)

AF:

0.00123

AC:

AN:

57546

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

197

295

394

492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

144

180

<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:

0.000873

AC:

133

AN:

152262

Hom.:

Cov.:

AF XY:

0.000833

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41578

American (AMR)

AF:

0.00157

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00137

AC:

AN:

67990

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.00111

Hom.:

Bravo

AF:

0.00104

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000546

AC:

ExAC

AF:

0.000253

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VSX1: BS1

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: Reported in 1 female with posterior polymorphous dystrophy (Vincent 2005).

Posterior polymorphous corneal dystrophy

Uncertain:1

May 10, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

VSX1-related disorder

Benign:1

Mar 07, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Keratoconus

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.054

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.68

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.099

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.7

PhyloP100

3.6

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.96

REVEL

Uncertain

0.56

Sift

Uncertain

0.0030

Sift4G

Benign

0.66

Polyphen

0.022

Vest4

0.29

MVP

0.75

MPC

0.11

ClinPred

0.038

GERP RS

-0.29

PromoterAI

-0.019

Neutral

(source)

Varity_R

0.041

gMVP

0.29

Mutation Taster

=1/99

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over