10-117134192-C-G

Variant names:

• chr10-117134192-C-G
• rs1255216202
• NM_001112704.2:c.821G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001112704.2(VAX1):​c.821G>C​(p.Ser274Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,361,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. S274I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: VAX1 NM_001112704.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.02
• Publications: 0 publications found

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]

VAX1 Gene-Disease associations (from GenCC):

• microphthalmia, syndromic 11

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31466472).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001112704.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAX1	NM_001112704.2	MANE Select	c.821G>C	p.Ser274Thr	missense	Exon 3 of 3	NP_001106175.1	Q5SQQ9-1
	VAX1	NM_199131.3		c.430-1715G>C		intron	N/A	NP_954582.1	Q5SQQ9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAX1	ENST00000369206.6	TSL:5 MANE Select	c.821G>C	p.Ser274Thr	missense	Exon 3 of 3	ENSP00000358207.4	Q5SQQ9-1
	VAX1	ENST00000277905.6	TSL:1	c.430-1715G>C		intron	N/A	ENSP00000277905.2	Q5SQQ9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000867 AC: 1 AN: 115344 AF XY: 0.00

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: 0.0000226

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1361222 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 671104

African (AFR) AF: 0.00 AC: 0 AN: 28104

American (AMR) AF: 0.00 AC: 0 AN: 29560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24240

East Asian (EAS) AF: 0.00 AC: 0 AN: 31194

South Asian (SAS) AF: 0.00 AC: 0 AN: 75142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5354

European-Non Finnish (NFE) AF: 9.40e-7 AC: 1 AN: 1063970

Other (OTH) AF: 0.00 AC: 0 AN: 56404

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.56	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.013	D
Sift4G	Benign	1.0	T
Polyphen		0.42	B
Vest4		0.33
MutPred		0.27		Loss of glycosylation at S274 (P = 0.0754)
MVP		0.73
MPC		0.93
ClinPred		0.25	T
GERP RS		3.2
Varity_R		0.15
gMVP		0.41
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs1255216202; hg19: chr10-118893703;