chr10-117134322-C-T

Variant names:

• chr10-117134322-C-T
• rs1253636317
• NM_001112704.2:c.691G>A

Variant summary

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

The NM_001112704.2(VAX1):​c.691G>A​(p.Ala231Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000489 in 1,022,082 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: VAX1 NM_001112704.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.292
• 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=0.29426837).

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.691G>A	p.Ala231Thr	missense	Exon 3 of 3	NP_001106175.1	Q5SQQ9-1
	VAX1	NM_199131.3		c.430-1845G>A		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.691G>A	p.Ala231Thr	missense	Exon 3 of 3	ENSP00000358207.4	Q5SQQ9-1
	VAX1	ENST00000277905.6	TSL:1	c.430-1845G>A		intron	N/A	ENSP00000277905.2	Q5SQQ9-2

Frequencies

GnomAD3 genomes AF: 0.00000683 AC: 1 AN: 146400 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000457 AC: 4 AN: 875682 Hom.: 0 Cov.: 32 AF XY: 0.00000245 AC XY: 1 AN XY: 408188

African (AFR) AF: 0.00 AC: 0 AN: 16696

American (AMR) AF: 0.00 AC: 0 AN: 2398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6260

East Asian (EAS) AF: 0.00 AC: 0 AN: 5592

South Asian (SAS) AF: 0.00 AC: 0 AN: 17692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1822

European-Non Finnish (NFE) AF: 0.00000506 AC: 4 AN: 790388

Other (OTH) AF: 0.00 AC: 0 AN: 29898

GnomAD4 genome AF: 0.00000683 AC: 1 AN: 146400 Hom.: 0 Cov.: 32 AF XY: 0.0000141 AC XY: 1 AN XY: 71150

African (AFR) AF: 0.00 AC: 0 AN: 40802

American (AMR) AF: 0.00 AC: 0 AN: 14750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 5010

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65938

Other (OTH) AF: 0.00 AC: 0 AN: 2022

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.29
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.10	N
REVEL	Benign	0.27
Sift	Benign	0.080	T
Sift4G	Benign	0.16	T
Polyphen		0.0070	B
Vest4		0.25
MutPred		0.30		Gain of glycosylation at A231 (P = 0)
MVP		0.66
MPC		1.3
ClinPred		0.19	T
GERP RS		3.3
Varity_R		0.077
gMVP		0.36
Mutation Taster		=90/10	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: rs1253636317; hg19: chr10-118893833;