16-52439588-C-T

Variant names:

• chr16-52439588-C-T
• rs772527716
• NM_001080430.4:c.1368G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080430.4(TOX3):​c.1368G>A​(p.Met456Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TOX3 NM_001080430.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.75
• Publications: 0 publications found

Genes affected

TOX3 (HGNC:11972): (TOX high mobility group box family member 3) The protein encoded by this gene contains an HMG-box, indicating that it may be involved in bending and unwinding of DNA and alteration of chromatin structure. The C-terminus of the encoded protein is glutamine-rich due to CAG repeats in the coding sequence. A minor allele of this gene has been implicated in an elevated risk of breast cancer. Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Apr 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15866858).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080430.4. 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
	TOX3	NM_001080430.4	MANE Select	c.1368G>A	p.Met456Ile	missense	Exon 7 of 7	NP_001073899.2	O15405-1
	TOX3	NM_001146188.2		c.1353G>A	p.Met451Ile	missense	Exon 8 of 8	NP_001139660.1	O15405-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOX3	ENST00000219746.14	TSL:2 MANE Select	c.1368G>A	p.Met456Ile	missense	Exon 7 of 7	ENSP00000219746.9	O15405-1
	TOX3	ENST00000912163.1		c.1428G>A	p.Met476Ile	missense	Exon 8 of 8	ENSP00000582222.1
	TOX3	ENST00000873102.1		c.1365G>A	p.Met455Ile	missense	Exon 7 of 7	ENSP00000543161.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Benign	0.76
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		5.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.43
MutPred		0.49		Gain of MoRF binding (P = 0.1776)
MVP		0.043
MPC		0.24
ClinPred		0.27	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.66
gMVP		0.13

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: rs772527716; hg19: chr16-52473500;