10-117134192-C-A

Variant summary

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

The NM_001112704.2(VAX1):c.821G>T(p.Ser274Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VAX1 NM_001112704.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAX1	NM_001112704.2	c.821G>T	p.Ser274Ile	missense_variant	3/3	ENST00000369206.6
VAX1	NM_199131.3	c.430-1715G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAX1	ENST00000369206.6	c.821G>T	p.Ser274Ile	missense_variant	3/3	5	NM_001112704.2	P1
VAX1	ENST00000277905.6	c.430-1715G>T		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microphthalmia, syndromic 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 16, 2022

This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 274 of the VAX1 protein (p.Ser274Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VAX1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.017
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.063	D
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.74	D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.13	T
Polyphen		0.94	P
Vest4		0.48
MutPred		0.45		Gain of sheet (P = 0.0149);
MVP		0.60
MPC		2.2
ClinPred		0.78	D
GERP RS		3.2
Varity_R		0.35
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-118893703;