rs16951186

chr16-52463960-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001080430.4(TOX3):c.382G>A(p.Val128Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,576,708 control chromosomes in the GnomAD database, including 1,577 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.061 (796 hom., cov: 33)
  • Exomes 𝑓: 0.014 (781 hom.)
• Consequence: TOX3 NM_001080430.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.695

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015140474).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOX3	NM_001080430.4	c.382G>A	p.Val128Met	missense_variant	3/7	ENST00000219746.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOX3	ENST00000219746.14	c.382G>A	p.Val128Met	missense_variant	3/7	2	NM_001080430.4	A2
TOX3	ENST00000407228.7	c.367G>A	p.Val123Met	missense_variant	4/8	2		P2
TOX3	ENST00000563091.1	c.274G>A	p.Val92Met	missense_variant	3/4	4

Frequencies

GnomAD3 genomes AF: 0.0611 AC: 9292 AN: 152092 Hom.: 793 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0263

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00930

Gnomad OTH AF: 0.0459

GnomAD3 exomes AF: 0.0211 AC: 4775 AN: 225930 Hom.: 311 AF XY: 0.0180 AC XY: 2199 AN XY: 122072

Gnomad AFR exome AF: 0.196

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.00446

Gnomad EAS exome AF: 0.000122

Gnomad SAS exome AF: 0.0154

Gnomad FIN exome AF: 0.000675

Gnomad NFE exome AF: 0.00940

Gnomad OTH exome AF: 0.0159

GnomAD4 exome AF: 0.0144 AC: 20475 AN: 1424498 Hom.: 781 Cov.: 30 AF XY: 0.0139 AC XY: 9789 AN XY: 705070

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.0150

Gnomad4 ASJ exome AF: 0.00536

Gnomad4 EAS exome AF: 0.0000525

Gnomad4 SAS exome AF: 0.0169

Gnomad4 FIN exome AF: 0.000968

Gnomad4 NFE exome AF: 0.00952

Gnomad4 OTH exome AF: 0.0219

GnomAD4 genome AF: 0.0611 AC: 9307 AN: 152210 Hom.: 796 Cov.: 33 AF XY: 0.0589 AC XY: 4385 AN XY: 74420

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.0262

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00931

Gnomad4 OTH AF: 0.0455

Alfa AF: 0.0350 Hom.: 252

Bravo AF: 0.0695

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.192 AC: 732

ESP6500EA AF: 0.00970 AC: 80

ExAC AF: 0.0239 AC: 2887

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	15
Dann	Benign	0.92
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.64	T;T;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.86	P;P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.17	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.28	T;T;.
Polyphen		0.11	.;B;.
Vest4		0.18
MPC		0.40
ClinPred		0.0064	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs16951186; hg19: chr16-52497872;