dbSNP rs74315433: VSX1:p.Gly160Val (chr20-25079460-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014588.6(VSX1):c.479G>T(p.Gly160Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000598 in 1,612,800 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. G160D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00053 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 11 hom. )

Consequence

VSX1
NM_014588.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.39

Publications

39 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: Laboratory for Molecular Medicine, G2P, 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=0.009346396).

BP6

Variant 20-25079460-C-A is Benign according to our data. Variant chr20-25079460-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 337962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000605 (883/1460580) while in subpopulation EAS AF = 0.0193 (768/39692). AF 95% confidence interval is 0.0182. There are 11 homozygotes in GnomAdExome4. There are 420 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 81 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	UniProt
VSX1	NM_014588.6	MANE Select	c.479G>T	p.Gly160Val	missense	Exon 2 of 5	NP_055403.2
VSX1	NM_001256272.2		c.479G>T	p.Gly160Val	missense	Exon 2 of 5	NP_001243201.1	Q9NZR4-8
VSX1	NM_199425.3		c.479G>T	p.Gly160Val	missense	Exon 2 of 3	NP_955457.1	Q9NZR4-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VSX1	ENST00000376709.9	TSL:1 MANE Select	c.479G>T	p.Gly160Val	missense	Exon 2 of 5	ENSP00000365899.3	Q9NZR4-1
VSX1	ENST00000429762.7	TSL:1	c.479G>T	p.Gly160Val	missense	Exon 2 of 5	ENSP00000401690.3	Q9NZR4-8
VSX1	ENST00000376707.4	TSL:1	c.479G>T	p.Gly160Val	missense	Exon 2 of 3	ENSP00000365897.3	Q9NZR4-2

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0148

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00101

AC:

251

AN:

249512

AF XY:

0.000845

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0122

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000605

AC:

883

AN:

1460580

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

420

AN XY:

726502

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.000202

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.0193

AC:

768

AN:

39692

South Asian (SAS)

AF:

0.000547

AC:

AN:

85858

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5350

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1111744

Other (OTH)

AF:

0.000564

AC:

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

129

172

215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000532

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41532

American (AMR)

AF:

0.000196

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0147

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00230

Hom.:

Bravo

AF:

0.000710

ExAC

AF:

0.00119

AC:

145

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Posterior polymorphous corneal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.15

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.040

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0093

MetaSVM

Uncertain

-0.018

MutationAssessor

Uncertain

2.2

PhyloP100

1.4

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.43

Sift

Benign

0.12

Sift4G

Benign

0.20

Polyphen

0.53

Vest4

0.35

MVP

0.92

MPC

0.14

ClinPred

0.018

GERP RS

3.7

Varity_R

0.19

gMVP

0.19

Mutation Taster

=89/11

polymorphism

(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

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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

Computational scores

Splicing

Publications

Other links and lift over