chr20-25079507-G-C

Position:

chr20-25079507-G-C

Variant summary

Our verdict is Benign. Variant got -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. 13/21 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 100939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 444 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VSX1	NM_014588.6 linkuse as main transcript	c.432C>G	p.Asp144Glu	missense_variant	2/5	ENST00000376709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VSX1	ENST00000376709.9 linkuse as main transcript	c.432C>G	p.Asp144Glu	missense_variant	2/5	1	NM_014588.6	P1	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

GnomAD3 exomes

AF:

0.00341

AC:

840

AN:

246288

Hom.:

AF XY:

0.00354

AC XY:

471

AN XY:

132996

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 SAS exome

AF:

0.00274

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

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.00189

Gnomad4 ASJ exome

AF:

0.0182

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00252

Gnomad4 FIN exome

AF:

0.00343

Gnomad4 NFE exome

AF:

0.00327

Gnomad4 OTH exome

AF:

0.00393

GnomAD4 genome

AF:

0.00292

AC:

444

AN:

152224

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

198

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000506

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.0173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.00321

Gnomad4 NFE

AF:

0.00384

Gnomad4 OTH

AF:

0.00427

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	VSX1: BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polymorphous corneal dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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

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

MutationTaster

Benign

1.0

D;D;D;D;D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over