NM_014729.3:c.1089C>A

Variant names:

• chr8-58815641-G-T
• NM_014729.3:c.1089C>A

Variant summary

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

The NM_014729.3(TOX):​c.1089C>A​(p.Ser363Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: TOX NM_014729.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22
• Publications: 0 publications found

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: 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=0.28799465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOX	NM_014729.3	c.1089C>A	p.Ser363Arg	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.1089C>A	p.Ser363Arg	missense_variant	Exon 7 of 9	1	NM_014729.3	ENSP00000354842.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 30, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1089C>A (p.S363R) alteration is located in exon 7 (coding exon 7) of the TOX gene. This alteration results from a C to A substitution at nucleotide position 1089, causing the serine (S) at amino acid position 363 to be replaced by an arginine (R). 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	Pathogenic	0.63
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.060
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.068
Sift	Benign	0.096	T
Sift4G	Uncertain	0.053	T
Polyphen		0.15	B
Vest4		0.54
MutPred		0.28		Gain of methylation at S363 (P = 0.0335);
MVP		0.082
MPC		0.32
ClinPred		0.42	T
GERP RS		6.1
Varity_R		0.089
gMVP		0.43
Mutation Taster		=78/22	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

hg19: chr8-59728200;