Genetic Variant VAX2:p.Thr44Met (chr2-70900752-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012476.3(VAX2):c.131C>T(p.Thr44Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,329,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T44K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

VAX2
NM_012476.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.281

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15639538).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAX2	NM_012476.3 link	c.131C>T	p.Thr44Met	missense_variant	Exon 1 of 3	ENST00000234392.3	NP_036608.1	Q9UIW0F1T0K5
VAX2	XM_011532750.4 link	c.131C>T	p.Thr44Met	missense_variant	Exon 1 of 4		XP_011531052.1
VAX2	XM_011532751.4 link	c.131C>T	p.Thr44Met	missense_variant	Exon 1 of 4		XP_011531053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAX2	ENST00000234392.3 link	c.131C>T	p.Thr44Met	missense_variant	Exon 1 of 3	1	NM_012476.3	ENSP00000234392.2		Q9UIW0
VAX2	ENST00000432367.6 link	n.-47C>T		upstream_gene_variant		5		ENSP00000405114.2		C9J5E3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000107

AC:

AN:

93108

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000309

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000150

AC:

AN:

1329612

Hom.:

Cov.:

AF XY:

0.00000153

AC XY:

AN XY:

655042

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27550

American (AMR)

AF:

0.00

AC:

AN:

29534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23540

East Asian (EAS)

AF:

0.00

AC:

AN:

29640

South Asian (SAS)

AF:

0.00

AC:

AN:

72622

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40700

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3928

European-Non Finnish (NFE)

AF:

0.00000191

AC:

AN:

1047278

Other (OTH)

AF:

0.00

AC:

AN:

54820

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000409

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.098

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.70

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.70

MutationAssessor

Benign

0.34

PhyloP100

-0.28

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.23

REVEL

Benign

0.13

Sift

Benign

0.060

Sift4G

Benign

0.11

Polyphen

0.47

Vest4

0.11

MutPred

0.18

Loss of glycosylation at T44 (P = 0.0112);

MVP

0.90

MPC

0.057

ClinPred

0.45

GERP RS

-4.0

PromoterAI

0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.015

gMVP

0.24

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over