Variant 2-70932789-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_012476.3(VAX2):c.458G>A(p.Arg153His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,568,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R153C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

VAX2
NM_012476.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.90

Variant links:

Genes affected

VAX2 (HGNC:12661): (ventral anterior homeobox 2) This gene encodes a homeobox protein and is almost exclusively expressed in the ventral portion of the retina during development. In mouse studies, this gene was found to be required for the correct formation of the optic fissure and other aspects of retinal development. [provided by RefSeq, Sep 2008]

VAX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAX2	NM_012476.3 linkuse as main transcript	c.458G>A	p.Arg153His	missense_variant	3/3	ENST00000234392.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
VAX2	ENST00000234392.3 linkuse as main transcript	c.458G>A	p.Arg153His	missense_variant	3/3	1	NM_012476.3	P1
VAX2	ENST00000432367.6 linkuse as main transcript	c.*45+8451G>A		intron_variant, NMD_transcript_variant		5
VAX2	ENST00000646783.1 linkuse as main transcript	c.80-6629G>A		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

146836

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000610

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000689

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000149

AC:

AN:

228312

Hom.:

AF XY:

0.000122

AC XY:

AN XY:

123336

show subpopulations

Gnomad AFR exome

AF:

0.000388

Gnomad AMR exome

AF:

0.000891

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:

0.00000955

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000549

AC:

AN:

1421776

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

703654

show subpopulations

Gnomad4 AFR exome

AF:

0.000899

Gnomad4 AMR exome

AF:

0.000734

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000265

Gnomad4 SAS exome

AF:

0.0000372

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.0000342

GnomAD4 genome

AF:

0.000177

AC:

AN:

146944

Hom.:

Cov.:

AF XY:

0.000196

AC XY:

AN XY:

71364

show subpopulations

Gnomad4 AFR

AF:

0.000608

Gnomad4 AMR

AF:

0.0000688

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000149

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000257

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The c.458G>A (p.R153H) alteration is located in exon 3 (coding exon 3) of the VAX2 gene. This alteration results from a G to A substitution at nucleotide position 458, causing the arginine (R) at amino acid position 153 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.88

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

0.99

Vest4

0.96

MVP

1.0

MPC

0.27

ClinPred

0.68

GERP RS

4.9

Varity_R

0.73

gMVP

0.65

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