rs74315436

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_014588.6(VSX1):c.50T>C(p.Leu17Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,538,166 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L17V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

VSX1
NM_014588.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0960

Publications

16 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 -6 ACMG points.

BP6

Variant 20-25082047-A-G is Benign according to our data. Variant chr20-25082047-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 5251.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 19 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSX1	NM_014588.6 link	c.50T>C	p.Leu17Pro	missense_variant	Exon 1 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.50T>C	p.Leu17Pro	missense_variant	Exon 1 of 5	1	NM_014588.6	ENSP00000365899.3

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000235

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000127

AC:

AN:

134222

AF XY:

0.000109

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000812

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000128

AC:

177

AN:

1385978

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

684176

show subpopulations

African (AFR)

AF:

0.0000313

AC:

AN:

32000

American (AMR)

AF:

0.000139

AC:

AN:

35942

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25160

East Asian (EAS)

AF:

0.00

AC:

AN:

36352

South Asian (SAS)

AF:

0.000113

AC:

AN:

79482

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33602

Middle Eastern (MID)

AF:

0.00351

AC:

AN:

5126

European-Non Finnish (NFE)

AF:

0.000126

AC:

136

AN:

1080380

Other (OTH)

AF:

0.000138

AC:

AN:

57934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.000125

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68020

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000391

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.0000839

AC:

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Keratoconus 1

Pathogenic:1

Jan 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

VSX1-related disorder

Uncertain:1

Feb 14, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The VSX1 c.50T>C variant is predicted to result in the amino acid substitution p.Leu17Pro. This variant has been reported in individuals with keratoconus (Bisceglia et al. 2005. PubMed ID: 15623752; De Bonis et al. 2011. PubMed ID: 21976959); however, it was noted in these studies that the variant displayed incomplete penetrance and variable expressivity. This variant is reported in 0.018% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is more common than expected for autosomal dominant disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine 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

0.074

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

.;.;T;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.66

T;T;T;T

M_CAP

Pathogenic

0.83

MetaRNN

Uncertain

0.62

D;D;D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.2

M;M;M;M

PhyloP100

-0.096

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.3

N;N;N;N

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0060

D;D;D;D

Sift4G

Benign

0.20

T;T;T;T

Polyphen

0.83

P;P;P;P

Vest4

0.25

MutPred

0.76

Loss of stability (P = 0.0026);Loss of stability (P = 0.0026);Loss of stability (P = 0.0026);Loss of stability (P = 0.0026);

MVP

0.89

MPC

0.67

ClinPred

0.13

GERP RS

0.73

PromoterAI

0.035

Neutral

(source)

Varity_R

0.26

gMVP

0.55

Mutation Taster

=0/100

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over