20-25078806-C-T

Variant names:

Variant summary

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

The ENST00000376707.4(VSX1):c.650G>A(p.Arg217His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,613,780 control chromosomes in the GnomAD database, including 36,196 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2832 hom., cov: 32)

Exomes 𝑓: 0.20 ( 33364 hom. )

Consequence

VSX1
ENST00000376707.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.159

Publications

55 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=7.990231E-5).

BP6

Variant 20-25078806-C-T is Benign according to our data. Variant chr20-25078806-C-T is described in ClinVar as Benign. ClinVar VariationId is 1684215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSX1	NM_014588.6 link	c.627+23G>A		intron_variant	Intron 3 of 4	ENST00000376709.9	NP_055403.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VSX1	ENST00000376709.9 link	c.627+23G>A		intron_variant	Intron 3 of 4	1	NM_014588.6	ENSP00000365899.3

Frequencies

GnomAD3 genomes

AF:

0.165

AC:

25082

AN:

151790

Hom.:

2834

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0396

Gnomad AMI

AF:

0.211

Gnomad AMR

AF:

0.220

Gnomad ASJ

AF:

0.172

Gnomad EAS

AF:

0.518

Gnomad SAS

AF:

0.176

Gnomad FIN

AF:

0.201

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.194

Gnomad OTH

AF:

0.189

GnomAD2 exomes

AF:

0.211

AC:

52980

AN:

251472

AF XY:

0.210

show subpopulations

Gnomad AFR exome

AF:

0.0350

Gnomad AMR exome

AF:

0.223

Gnomad ASJ exome

AF:

0.180

Gnomad EAS exome

AF:

0.510

Gnomad FIN exome

AF:

0.198

Gnomad NFE exome

AF:

0.199

Gnomad OTH exome

AF:

0.206

GnomAD4 exome

AF:

0.204

AC:

297675

AN:

1461874

Hom.:

33364

Cov.:

AF XY:

0.203

AC XY:

147591

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0318

AC:

1063

AN:

33480

American (AMR)

AF:

0.224

AC:

10023

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

4713

AN:

26136

East Asian (EAS)

AF:

0.544

AC:

21590

AN:

39700

South Asian (SAS)

AF:

0.173

AC:

14937

AN:

86258

European-Finnish (FIN)

AF:

0.192

AC:

10276

AN:

53416

Middle Eastern (MID)

AF:

0.189

AC:

1091

AN:

5768

European-Non Finnish (NFE)

AF:

0.200

AC:

222199

AN:

1111996

Other (OTH)

AF:

0.195

AC:

11783

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

15506

31013

46519

62026

77532

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7878

15756

23634

31512

39390

<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:

0.165

AC:

25081

AN:

151906

Hom.:

2832

Cov.:

AF XY:

0.170

AC XY:

12646

AN XY:

74234

show subpopulations

African (AFR)

AF:

0.0395

AC:

1637

AN:

41440

American (AMR)

AF:

0.220

AC:

3354

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

596

AN:

3468

East Asian (EAS)

AF:

0.518

AC:

2666

AN:

5146

South Asian (SAS)

AF:

0.176

AC:

842

AN:

4784

European-Finnish (FIN)

AF:

0.201

AC:

2120

AN:

10546

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.194

AC:

13212

AN:

67946

Other (OTH)

AF:

0.191

AC:

402

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

994

1988

2983

3977

4971

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

274

548

822

1096

1370

<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:

0.190

Hom.:

10595

Bravo

AF:

0.164

TwinsUK

AF:

0.207

AC:

767

ALSPAC

AF:

0.191

AC:

736

ESP6500AA

AF:

0.0433

AC:

191

ESP6500EA

AF:

0.198

AC:

1700

ExAC

AF:

0.206

AC:

25047

Asia WGS

AF:

0.300

AC:

1043

AN:

3478

EpiCase

AF:

0.194

EpiControl

AF:

0.193

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Keratoconus 1

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.41

CADD

Benign

3.5

(source)

DANN

Benign

0.86

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0094

LIST_S2

Benign

0.31

MetaRNN

Benign

0.000080

MetaSVM

Benign

-0.96

PhyloP100

0.16

PROVEAN

Benign

2.6

REVEL

Benign

0.18

Sift

Benign

0.049

Polyphen

0.0080

Vest4

0.012

ClinPred

0.0018

GERP RS

-4.9

Mutation Taster

=100/0

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

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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