Genetic Variant TOX3:c.88-31681A>G (chr16-52500255-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_001080430.4(TOX3):c.88-31681A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.608 (AC=92,509) in the gnomAD database across 152,040 control chromosomes, including 28,673 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.796. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.61 ( 28673 hom., cov: 32)

Consequence

TOX3
NM_001080430.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.569

Publications

58 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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new If you want to explore the variant's impact on the transcript NM_001080430.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -12 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.7963 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001080430.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOX3	NM_001080430.4	MANE Select	c.88-31681A>G		intron	N/A	NP_001073899.2	O15405-1
	TOX3	NM_001146188.2		c.75+19151A>G		intron	N/A	NP_001139660.1	O15405-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TOX3	ENST00000219746.14	TSL:2 MANE Select	c.88-31681A>G	intron	N/A	ENSP00000219746.9	O15405-1
TOX3	ENST00000912163.1		c.88-31681A>G	intron	N/A	ENSP00000582222.1	A0ACI8SKH9
TOX3	ENST00000873102.1		c.88-31681A>G	intron	N/A	ENSP00000543161.1	A0ACI8R9S9

Frequencies

GnomAD3 genomes

AF:

0.608

AC:

92442

AN:

151924

Hom.:

28642

Cov.:

show subpopulations

Gnomad AFR

AF:

0.689

Gnomad AMI

AF:

0.496

Gnomad AMR

AF:

0.575

Gnomad ASJ

AF:

0.567

Gnomad EAS

AF:

0.817

Gnomad SAS

AF:

0.700

Gnomad FIN

AF:

0.519

Gnomad MID

AF:

0.598

Gnomad NFE

AF:

0.562

Gnomad OTH

AF:

0.608

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.608

AC:

92509

AN:

152040

Hom.:

28673

Cov.:

AF XY:

0.610

AC XY:

45379

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.688

AC:

28519

AN:

41432

American (AMR)

AF:

0.576

AC:

8798

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.567

AC:

1967

AN:

3470

East Asian (EAS)

AF:

0.817

AC:

4223

AN:

5170

South Asian (SAS)

AF:

0.701

AC:

3378

AN:

4822

European-Finnish (FIN)

AF:

0.519

AC:

5495

AN:

10578

Middle Eastern (MID)

AF:

0.588

AC:

173

AN:

294

European-Non Finnish (NFE)

AF:

0.562

AC:

38230

AN:

67968

Other (OTH)

AF:

0.604

AC:

1274

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1844

3687

5531

7374

9218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

770

1540

2310

3080

3850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

AF:

0.614

AC:

162397

AN:

264690

Hom.:

50587

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.579

AC:

188548

AN:

325382

Hom.:

55109

Local populations

ABraOM SABE-WGS-1171

AF:

0.629

AC:

1472

AN:

2342

Hom.:

470

ChinaMAP Phase 1

AF:

0.821

Denmark Genome

AF:

0.533

AC:

160

AN:

300

GenomeAsia100K

AF:

0.730

AC:

2539

AN:

3478

show subpopulations

Oceania

AF:

0.480

AC:

AN:

148

Hom.:

North-East Asia

AF:

0.766

AC:

538

AN:

702

Hom.:

202

South-East Asia

AF:

0.832

AC:

576

AN:

692

Hom.:

243

South Asia

AF:

0.744

AC:

1077

AN:

1448

Hom.:

409

Africa

AF:

0.601

AC:

125

AN:

208

Hom.:

America

AF:

0.519

AC:

AN:

Hom.:

West Eurasia

AF:

0.548

AC:

125

AN:

228

Hom.:

Korea4K (4,157 Koreans)

AF:

0.795

AC:

5753

AN:

7234

Qatari Genome

AF:

0.494

AC:

AN:

176

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.790

AC:

96992

AN:

122792

Hom.:

38425

Turkish Variome

AF:

0.607

AC:

938

AN:

1546

Hom.:

279

UK10K

AF:

0.555

AC:

4197

AN:

7562

show subpopulations

TwinsUK

AF:

0.553

AC:

1975

AN:

3574

ALSPAC

AF:

0.557

AC:

2147

AN:

3854

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.824

AC:

7386

AN:

8960

Hom.:

3068

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.55

(source)

DANN

Benign

0.35

PhyloP100

-0.57

AlphaGenome AVI

Benign

2.4

(source)

GPN-Star LLR

2.1

(source)

GPN-Star score

-2.1

(source)

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

Pangolin (max)

Benign

0.0

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over