10-117134130-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001112704.2(VAX1):c.883A>G(p.Met295Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000495 in 1,535,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: VAX1 NM_001112704.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.49

Genes affected

VAX1 (HGNC:12660): (ventral anterior homeobox 1) This gene encodes a homeo-domain containing protein from a class of homeobox transcription factors which are conserved in vertebrates. Genes of this family are involved in the regulation of body development and morphogenesis. The most conserved genes, called HOX genes are found in special gene clusters. This gene belongs to the VAX subfamily and lies in the vicinity of the EMX homeobox gene family. Another member of VAX family is located on chromosome 2. The encoded protein may play an important role in the development of anterior ventral forebrain and visual system. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.110079646).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAX1	NM_001112704.2	c.883A>G	p.Met295Val	missense_variant	3/3	ENST00000369206.6
VAX1	NM_199131.3	c.430-1653A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAX1	ENST00000369206.6	c.883A>G	p.Met295Val	missense_variant	3/3	5	NM_001112704.2	P1
VAX1	ENST00000277905.6	c.430-1653A>G		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.000290 AC: 44 AN: 151954 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.0000785 AC: 11 AN: 140080 Hom.: 0 AF XY: 0.0000803 AC XY: 6 AN XY: 74682

Gnomad AFR exome AF: 0.000655

Gnomad AMR exome AF: 0.000326

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: 0.0000231 AC: 32 AN: 1383794 Hom.: 0 Cov.: 32 AF XY: 0.0000147 AC XY: 10 AN XY: 682290

Gnomad4 AFR exome AF: 0.000432

Gnomad4 AMR exome AF: 0.000298

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.32e-7

Gnomad4 OTH exome AF: 0.000122

GnomAD4 genome AF: 0.000290 AC: 44 AN: 151954 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74208

Gnomad4 AFR AF: 0.000893

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00192

Alfa AF: 0.000226 Hom.: 0

Bravo AF: 0.000423

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.883A>G (p.M295V) alteration is located in exon 3 (coding exon 3) of the VAX1 gene. This alteration results from a A to G substitution at nucleotide position 883, causing the methionine (M) at amino acid position 295 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 06, 2015

- -

Microphthalmia, syndromic 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 196313). This variant has not been reported in the literature in individuals affected with VAX1-related conditions. This variant is present in population databases (rs794727489, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 295 of the VAX1 protein (p.Met295Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	21
Dann	Benign	0.72
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.71	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.87	N
REVEL	Uncertain	0.30
Sift	Benign	0.13	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.22		Gain of glycosylation at S298 (P = 0.1307);
MVP		0.64
MPC		0.96
ClinPred		0.014	T
GERP RS		4.1
Varity_R		0.25
gMVP		0.58

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

Other links and lift over

dbSNP: rs794727489; hg19: chr10-118893641;