Genetic Variant TOX3:p.Val128Met (chr16-52463960-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.061 ( 796 hom., cov: 33)

Exomes 𝑓: 0.014 ( 781 hom. )

Consequence

TOX3
NM_001080430.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.695

Publications

9 publications found

Variant links:

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]

TOX3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TOX3	NM_001080430.4 link	c.382G>A	p.Val128Met	missense_variant	Exon 3 of 7	ENST00000219746.14	NP_001073899.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TOX3	ENST00000219746.14 link	c.382G>A	p.Val128Met	missense_variant	Exon 3 of 7	2	NM_001080430.4	ENSP00000219746.9
TOX3	ENST00000407228.7 link	c.367G>A	p.Val123Met	missense_variant	Exon 4 of 8	2		ENSP00000385705.3
TOX3	ENST00000563091.1 link	c.274G>A	p.Val92Met	missense_variant	Exon 3 of 4	4		ENSP00000457401.1
TOX3	ENST00000568436.1 link	n.*306G>A		downstream_gene_variant		3		ENSP00000463843.1

Frequencies

GnomAD3 genomes

AF:

0.0611

AC:

9292

AN:

152092

Hom.:

793

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0211

AC:

4775

AN:

225930

AF XY:

0.0180

show subpopulations

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 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.:

AF XY:

0.0139

AC XY:

9789

AN XY:

705070

show subpopulations

African (AFR)

AF:

0.201

AC:

6517

AN:

32502

American (AMR)

AF:

0.0150

AC:

608

AN:

40418

Ashkenazi Jewish (ASJ)

AF:

0.00536

AC:

132

AN:

24642

East Asian (EAS)

AF:

0.0000525

AC:

AN:

38120

South Asian (SAS)

AF:

0.0169

AC:

1353

AN:

80208

European-Finnish (FIN)

AF:

0.000968

AC:

AN:

52678

Middle Eastern (MID)

AF:

0.0238

AC:

134

AN:

5636

European-Non Finnish (NFE)

AF:

0.00952

AC:

10387

AN:

1091346

Other (OTH)

AF:

0.0219

AC:

1291

AN:

58948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

950

1899

2849

3798

4748

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

506

1012

1518

2024

2530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0611

AC:

9307

AN:

152210

Hom.:

796

Cov.:

AF XY:

0.0589

AC XY:

4385

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.195

AC:

8074

AN:

41500

American (AMR)

AF:

0.0262

AC:

401

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.0143

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000660

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00931

AC:

633

AN:

68024

Other (OTH)

AF:

0.0455

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

405

810

1216

1621

2026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0357

Hom.:

371

Bravo

AF:

0.0695

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.192

AC:

732

ESP6500EA

AF:

0.00970

AC:

ExAC

AF:

0.0239

AC:

2887

Asia WGS

AF:

0.0160

AC:

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

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.017

.;T;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.64

T;T;T

MetaRNN

Benign

0.0015

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L;.

PhyloP100

0.69

PrimateAI

Benign

0.47

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

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.029

gMVP

0.26

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over