Genetic Variant TOX3:c.906+135T>A (chr16-52445859-A-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.906+135T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 836,134 control chromosomes in the GnomAD database, including 39,053 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.26 ( 5890 hom., cov: 33)

Exomes 𝑓: 0.30 ( 33163 hom. )

Consequence

TOX3
NM_001080430.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.104

Publications

4 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 (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOX3	NM_001080430.4	MANE Select	c.906+135T>A		intron	N/A	NP_001073899.2
	TOX3	NM_001146188.2		c.891+135T>A		intron	N/A	NP_001139660.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TOX3	ENST00000219746.14	TSL:2 MANE Select	c.906+135T>A	intron	N/A	ENSP00000219746.9
TOX3	ENST00000407228.7	TSL:2	c.891+135T>A	intron	N/A	ENSP00000385705.3
TOX3	ENST00000566696.1	TSL:2	n.-133T>A	upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.261

AC:

39745

AN:

152060

Hom.:

5888

Cov.:

show subpopulations

Gnomad AFR

AF:

0.145

Gnomad AMI

AF:

0.309

Gnomad AMR

AF:

0.322

Gnomad ASJ

AF:

0.252

Gnomad EAS

AF:

0.634

Gnomad SAS

AF:

0.359

Gnomad FIN

AF:

0.286

Gnomad MID

AF:

0.275

Gnomad NFE

AF:

0.279

Gnomad OTH

AF:

0.284

GnomAD4 exome

AF:

0.298

AC:

204066

AN:

683956

Hom.:

33163

Cov.:

AF XY:

0.300

AC XY:

104508

AN XY:

348880

show subpopulations

African (AFR)

AF:

0.145

AC:

2409

AN:

16670

American (AMR)

AF:

0.341

AC:

6448

AN:

18910

Ashkenazi Jewish (ASJ)

AF:

0.254

AC:

3831

AN:

15092

East Asian (EAS)

AF:

0.630

AC:

20264

AN:

32144

South Asian (SAS)

AF:

0.342

AC:

16217

AN:

47466

European-Finnish (FIN)

AF:

0.297

AC:

11728

AN:

39460

Middle Eastern (MID)

AF:

0.301

AC:

1013

AN:

3362

European-Non Finnish (NFE)

AF:

0.277

AC:

132073

AN:

477322

Other (OTH)

AF:

0.301

AC:

10083

AN:

33530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

6775

13551

20326

27102

33877

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3100

6200

9300

12400

15500

<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:

0.261

AC:

39743

AN:

152178

Hom.:

5890

Cov.:

AF XY:

0.268

AC XY:

19955

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.145

AC:

6014

AN:

41518

American (AMR)

AF:

0.322

AC:

4934

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.252

AC:

874

AN:

3472

East Asian (EAS)

AF:

0.633

AC:

3262

AN:

5156

South Asian (SAS)

AF:

0.358

AC:

1722

AN:

4816

European-Finnish (FIN)

AF:

0.286

AC:

3035

AN:

10594

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.279

AC:

18940

AN:

67998

Other (OTH)

AF:

0.283

AC:

598

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1462

2924

4385

5847

7309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

418

836

1254

1672

2090

<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:

0.251

Hom.:

644

Bravo

AF:

0.261

Asia WGS

AF:

0.467

AC:

1620

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.89

(source)

DANN

Benign

0.64

PhyloP100

0.10

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over