Variant rs74315435 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014588.6(VSX1):c.766G>T(p.Ala256Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,550,320 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A256A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00063 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

VSX1
NM_014588.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 1.41

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009385645).

BS2

High AC in GnomAd at 90 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VSX1	NM_014588.6 linkuse as main transcript	c.766G>T	p.Ala256Ser	missense_variant	4/5	ENST00000376709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VSX1	ENST00000376709.9 linkuse as main transcript	c.766G>T	p.Ala256Ser	missense_variant	4/5	1	NM_014588.6	P1	Q9NZR4-1

Frequencies

GnomAD3 genomes

AF:

0.000592

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00208

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000984

AC:

AN:

152504

Hom.:

AF XY:

0.0000493

AC XY:

AN XY:

81108

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.0000812

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1398126

Hom.:

Cov.:

AF XY:

0.0000348

AC XY:

AN XY:

689626

show subpopulations

Gnomad4 AFR exome

AF:

0.00177

Gnomad4 AMR exome

AF:

0.0000560

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000185

Gnomad4 OTH exome

AF:

0.000104

GnomAD4 genome

AF:

0.000631

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.00222

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000208

Hom.:

Bravo

AF:

0.000672

ESP6500AA

AF:

0.00200

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000783

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Craniofacial anomalies and anterior segment dysgenesis syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2004

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.055

MetaRNN

Benign

0.0094

T;T

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

1.7

L;L

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.5

D;D

REVEL

Benign

0.28

Sift

Uncertain

0.017

D;D

Sift4G

Uncertain

0.027

D;D

Polyphen

0.34

B;P

Vest4

0.42

MVP

0.81

MPC

0.11

ClinPred

0.072

GERP RS

2.5

Varity_R

0.16

gMVP

0.67

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