Genetic Variant ENST00000376707.4:c.650G>A (chr20-25078806-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -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. 12/14 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

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 -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 id is 1684215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-25078806-C-T is described in Lovd as [Benign].

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	Q9NZR4-1

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		Q9NZR4-1

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

GnomAD3 exomes

AF:

0.211

AC:

52980

AN:

251472

Hom.:

6765

AF XY:

0.210

AC XY:

28544

AN XY:

135918

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 SAS exome

AF:

0.176

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

Gnomad4 AFR exome

AF:

0.0318

Gnomad4 AMR exome

AF:

0.224

Gnomad4 ASJ exome

AF:

0.180

Gnomad4 EAS exome

AF:

0.544

Gnomad4 SAS exome

AF:

0.173

Gnomad4 FIN exome

AF:

0.192

Gnomad4 NFE exome

AF:

0.200

Gnomad4 OTH exome

AF:

0.195

GnomAD4 genome

AF:

0.165

AC:

25081

AN:

151906

Hom.:

2832

Cov.:

AF XY:

0.170

AC XY:

12646

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.0395

Gnomad4 AMR

AF:

0.220

Gnomad4 ASJ

AF:

0.172

Gnomad4 EAS

AF:

0.518

Gnomad4 SAS

AF:

0.176

Gnomad4 FIN

AF:

0.201

Gnomad4 NFE

AF:

0.194

Gnomad4 OTH

AF:

0.191

Alfa

AF:

0.197

Hom.:

8179

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

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.41

CADD

Benign

3.5

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

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

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