rs1554942980

Positions:

• chr10-117136588-T-TG

Variant summary

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

The NM_001112704.2(VAX1):​c.312_313insC​(p.Thr105HisfsTer34) variant causes a frameshift 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: 33)
• Consequence: VAX1 NM_001112704.2 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0930

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	Protein	UniProt
VAX1	NM_001112704.2	c.312_313insC	p.Thr105HisfsTer34	frameshift_variant	2/3	ENST00000369206.6	NP_001106175.1
VAX1	NM_199131.3	c.312_313insC	p.Thr105HisfsTer34	frameshift_variant	2/4		NP_954582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VAX1	ENST00000369206.6	c.312_313insC	p.Thr105HisfsTer34	frameshift_variant	2/3	5	NM_001112704.2	ENSP00000358207	P1
VAX1	ENST00000277905.6	c.312_313insC	p.Thr105HisfsTer34	frameshift_variant	2/4	1		ENSP00000277905

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Labcorp Genetics (formerly Invitae), Labcorp

Apr 23, 2017

The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in VAX1 cause disease. Therefore, this variant has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a VAX1-related disease. This sequence change inserts 1 nucleotide in exon 2 of the VAX1 mRNA (c.312dupC), causing a frameshift at codon 105. This creates a premature translational stop signal (p.Thr105Hisfs*34) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1554942980; hg19: chr10-118896099;