chr20-25079507-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_014588.6(VSX1):c.432C>G(p.Asp144Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,611,518 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 28 hom. )

Consequence

VSX1
NM_014588.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.567

Publications

30 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070255995).

BP6

Variant 20-25079507-G-C is Benign according to our data. Variant chr20-25079507-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 100939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 444 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSX1	NM_014588.6 link	c.432C>G	p.Asp144Glu	missense_variant	Exon 2 of 5	ENST00000376709.9	NP_055403.2	Q9NZR4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VSX1	ENST00000376709.9 link	c.432C>G	p.Asp144Glu	missense_variant	Exon 2 of 5	1	NM_014588.6	ENSP00000365899.3		Q9NZR4-1

Frequencies

GnomAD3 genomes

AF:

0.00293

AC:

445

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00197

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00321

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00384

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00341

AC:

840

AN:

246288

AF XY:

0.00354

show subpopulations

Gnomad AFR exome

AF:

0.000442

Gnomad AMR exome

AF:

0.00152

Gnomad ASJ exome

AF:

0.0181

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.00391

Gnomad NFE exome

AF:

0.00375

Gnomad OTH exome

AF:

0.00314

GnomAD4 exome

AF:

0.00336

AC:

4903

AN:

1459294

Hom.:

Cov.:

AF XY:

0.00340

AC XY:

2464

AN XY:

725600

show subpopulations

African (AFR)

AF:

0.000359

AC:

AN:

33462

American (AMR)

AF:

0.00189

AC:

AN:

44544

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

475

AN:

26044

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00252

AC:

215

AN:

85478

European-Finnish (FIN)

AF:

0.00343

AC:

183

AN:

53316

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00327

AC:

3635

AN:

1110750

Other (OTH)

AF:

0.00393

AC:

237

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

238

475

713

950

1188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

130

260

390

520

650

<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:

0.00292

AC:

444

AN:

152224

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

198

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

41540

American (AMR)

AF:

0.00196

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00332

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00321

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00384

AC:

261

AN:

68010

Other (OTH)

AF:

0.00427

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

114

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:

0.00410

Hom.:

Bravo

AF:

0.00296

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00334

AC:

405

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VSX1: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polymorphous corneal dystrophy

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

.;.;T;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.50

T;T;T;T

M_CAP

Benign

0.064

MetaRNN

Benign

0.0070

T;T;T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.4

L;L;L;L

PhyloP100

0.57

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.3

N;N;N;N

REVEL

Uncertain

0.36

Sift

Benign

0.12

T;T;T;T

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.027

B;B;B;B

Vest4

0.23

MutPred

0.16

Gain of glycosylation at T140 (P = 0.2766);Gain of glycosylation at T140 (P = 0.2766);Gain of glycosylation at T140 (P = 0.2766);Gain of glycosylation at T140 (P = 0.2766);

MVP

0.86

MPC

0.097

ClinPred

0.017

GERP RS

1.8

Varity_R

0.10

gMVP

0.17

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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