8-58815703-C-T

Variant names:

• chr8-58815703-C-T
• rs374396949
• NM_014729.3:c.1027G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014729.3(TOX):​c.1027G>A​(p.Val343Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000391 in 1,612,142 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: TOX NM_014729.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.48

Genes affected

TOX (HGNC:18988): (thymocyte selection associated high mobility group box) The protein encoded by this gene contains a HMG box DNA binding domain. HMG boxes are found in many eukaryotic proteins involved in chromatin assembly, transcription and replication. This protein may function to regulate T-cell development.[provided by RefSeq, Apr 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08932775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOX	NM_014729.3	c.1027G>A	p.Val343Met	missense_variant	Exon 7 of 9	ENST00000361421.2	NP_055544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOX	ENST00000361421.2	c.1027G>A	p.Val343Met	missense_variant	Exon 7 of 9	1	NM_014729.3	ENSP00000354842.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000724 AC: 18 AN: 248510 AF XY: 0.0000745

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000288 AC: 42 AN: 1460068 Hom.: 0 Cov.: 31 AF XY: 0.0000386 AC XY: 28 AN XY: 726222

African (AFR) AF: 0.0000299 AC: 1 AN: 33452

American (AMR) AF: 0.000291 AC: 13 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25974

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39676

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85970

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111040

Other (OTH) AF: 0.0000331 AC: 2 AN: 60338

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74264

African (AFR) AF: 0.0000242 AC: 1 AN: 41392

American (AMR) AF: 0.00124 AC: 19 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000284 Hom.: 0

Bravo AF: 0.000121

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1027G>A (p.V343M) alteration is located in exon 7 (coding exon 7) of the TOX gene. This alteration results from a G to A substitution at nucleotide position 1027, causing the valine (V) at amino acid position 343 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.090
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.20
Sift	Benign	0.14	T
Sift4G	Uncertain	0.058	T
Polyphen		0.51	P
Vest4		0.45
MVP		0.14
MPC		0.36
ClinPred		0.028	T
GERP RS		6.1
Varity_R		0.075
gMVP		0.55
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

dbSNP: rs374396949; hg19: chr8-59728262;