20-25081706-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014588.6(VSX1):c.391C>A(p.Arg131Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00694 in 1,505,368 control chromosomes in the GnomAD database, including 562 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 291 hom., cov: 33)

Exomes 𝑓: 0.0038 ( 271 hom. )

Consequence

VSX1
NM_014588.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.778

Publications

17 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016133189).

BP6

Variant 20-25081706-G-T is Benign according to our data. Variant chr20-25081706-G-T is described in ClinVar as Benign. ClinVar VariationId is 337965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSX1	NM_014588.6 link	c.391C>A	p.Arg131Ser	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.391C>A	p.Arg131Ser	missense_variant	Exon 1 of 5	1	NM_014588.6	ENSP00000365899.3

Frequencies

GnomAD3 genomes

AF:

0.0350

AC:

5329

AN:

152094

Hom.:

284

Cov.:

show subpopulations

Gnomad AFR

AF:

0.121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0139

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00962

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.0287

GnomAD2 exomes

AF:

0.00718

AC:

738

AN:

102810

AF XY:

0.00591

show subpopulations

Gnomad AFR exome

AF:

0.142

Gnomad AMR exome

AF:

0.00715

Gnomad ASJ exome

AF:

0.00374

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000763

Gnomad OTH exome

AF:

0.00743

GnomAD4 exome

AF:

0.00376

AC:

5083

AN:

1353160

Hom.:

271

Cov.:

AF XY:

0.00340

AC XY:

2266

AN XY:

666934

show subpopulations

African (AFR)

AF:

0.135

AC:

3847

AN:

28520

American (AMR)

AF:

0.00800

AC:

257

AN:

32126

Ashkenazi Jewish (ASJ)

AF:

0.00264

AC:

AN:

23472

East Asian (EAS)

AF:

0.00

AC:

AN:

33382

South Asian (SAS)

AF:

0.000467

AC:

AN:

74944

European-Finnish (FIN)

AF:

0.0000296

AC:

AN:

33728

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

3940

European-Non Finnish (NFE)

AF:

0.000225

AC:

240

AN:

1066634

Other (OTH)

AF:

0.0104

AC:

587

AN:

56414

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

269

539

808

1078

1347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<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:

0.0352

AC:

5358

AN:

152208

Hom.:

291

Cov.:

AF XY:

0.0338

AC XY:

2514

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.121

AC:

5036

AN:

41556

American (AMR)

AF:

0.0138

AC:

212

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

67968

Other (OTH)

AF:

0.0284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

258

517

775

1034

1292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.00575

Hom.:

Bravo

AF:

0.0409

ESP6500AA

AF:

0.0922

AC:

328

ESP6500EA

AF:

0.00192

AC:

ExAC

AF:

0.00544

AC:

332

Asia WGS

AF:

0.00752

AC:

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 19, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30090183, 15051220)

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Posterior polymorphous corneal dystrophy

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.32

CADD

Benign

4.6

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.0

.;.;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.56

T;T;T;T

MetaRNN

Benign

0.0016

T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.34

N;N;N;N

PhyloP100

-0.78

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.64

N;N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.45

T;T;T;T

Sift4G

Benign

0.76

T;T;T;T

Vest4

0.057

ClinPred

0.0017

GERP RS

-3.9

PromoterAI

-0.016

Neutral

(source)

Varity_R

0.086

gMVP

0.27

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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