rs75395981

Positions:

chr14-74260704-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000261980.3(VSX2):c.871G>A(p.Asp291Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0132 in 1,593,940 control chromosomes in the GnomAD database, including 542 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D291D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.017 ( 82 hom., cov: 33)

Exomes 𝑓: 0.013 ( 460 hom. )

Consequence

VSX2
ENST00000261980.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 6.91

Variant links:

Genes affected

VSX2 (HGNC:1975): (visual system homeobox 2) This gene encodes a homeobox protein originally described as a retina-specific transcription factor. Mutations in this gene are associated with microphthalmia, cataracts and iris abnormalities. [provided by RefSeq, Oct 2009]

VSX2 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=0.0015234649).

BP6

Variant 14-74260704-G-A is Benign according to our data. Variant chr14-74260704-G-A is described in ClinVar as [Benign]. Clinvar id is 197895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-74260704-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VSX2	NM_182894.3 linkuse as main transcript	c.871G>A	p.Asp291Asn	missense_variant	5/5	ENST00000261980.3	NP_878314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VSX2	ENST00000261980.3 linkuse as main transcript	c.871G>A	p.Asp291Asn	missense_variant	5/5	1	NM_182894.3	ENSP00000261980	P1

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2617

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00654

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0861

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.0276

Gnomad SAS

AF:

0.0331

Gnomad FIN

AF:

0.00574

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00810

Gnomad OTH

AF:

0.0191

GnomAD3 exomes

AF:

0.0303

AC:

6417

AN:

211694

Hom.:

322

AF XY:

0.0263

AC XY:

3006

AN XY:

114172

show subpopulations

Gnomad AFR exome

AF:

0.00642

Gnomad AMR exome

AF:

0.128

Gnomad ASJ exome

AF:

0.0228

Gnomad EAS exome

AF:

0.0274

Gnomad SAS exome

AF:

0.0281

Gnomad FIN exome

AF:

0.00651

Gnomad NFE exome

AF:

0.00882

Gnomad OTH exome

AF:

0.0227

GnomAD4 exome

AF:

0.0128

AC:

18381

AN:

1441608

Hom.:

460

Cov.:

AF XY:

0.0126

AC XY:

9021

AN XY:

714970

show subpopulations

Gnomad4 AFR exome

AF:

0.00554

Gnomad4 AMR exome

AF:

0.120

Gnomad4 ASJ exome

AF:

0.0243

Gnomad4 EAS exome

AF:

0.0237

Gnomad4 SAS exome

AF:

0.0259

Gnomad4 FIN exome

AF:

0.00641

Gnomad4 NFE exome

AF:

0.00747

Gnomad4 OTH exome

AF:

0.0154

GnomAD4 genome

AF:

0.0173

AC:

2635

AN:

152332

Hom.:

Cov.:

AF XY:

0.0189

AC XY:

1406

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00678

Gnomad4 AMR

AF:

0.0863

Gnomad4 ASJ

AF:

0.0213

Gnomad4 EAS

AF:

0.0276

Gnomad4 SAS

AF:

0.0335

Gnomad4 FIN

AF:

0.00574

Gnomad4 NFE

AF:

0.00810

Gnomad4 OTH

AF:

0.0194

Alfa

AF:

0.0120

Hom.:

Bravo

AF:

0.0233

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.0112

AC:

ESP6500AA

AF:

0.00525

AC:

ESP6500EA

AF:

0.0107

AC:

ExAC

AF:

0.0221

AC:

2677

Asia WGS

AF:

0.0420

AC:

145

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Isolated microphthalmia 2

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Microphthalmia, isolated, with coloboma 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 29, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Benign

-0.065

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.2

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.8

REVEL

Benign

0.26

Sift

Benign

0.035

Sift4G

Benign

0.24

Polyphen

0.13

Vest4

0.090

MPC

0.21

ClinPred

0.015

GERP RS

4.8

Varity_R

0.11

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

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

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