NM_001080430.4:c.88-31681A>G

Variant names:

• chr16-52500255-T-C
• rs8051542
• NM_001080430.4:c.88-31681A>G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.569
• Publications: 58 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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		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	Intron 1 of 6	Prot: NP_001073899.2 UniProt:
	TOX3 NM_001146188.2		c.75+19151A>G	intron	Intron 2 of 7	Prot: NP_001139660.1 UniProt:

TOX3 NM_001080430.4

MANE Select

HGVSc / HGVSpc.88-31681A>G

Exon rankIntron 1 of 6

intron

Prot: NP_001073899.2UniProt: O15405-1

TOX3 NM_001146188.2

HGVSc / HGVSpc.75+19151A>G

Exon rankIntron 2 of 7

intron

Prot: NP_001139660.1UniProt: O15405-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TOX3 ENST00000219746.14	TSL:2MANE Select	c.88-31681A>G	intron	Intron 1 of 6	Prot: ENSP00000219746.9 UniProt:
	TOX3 ENST00000912163.1		c.88-31681A>G	intron	Intron 1 of 7	Prot: ENSP00000582222.1 UniProt:
	TOX3 ENST00000873102.1		c.88-31681A>G	intron	Intron 1 of 6	Prot: ENSP00000543161.1 UniProt:

TOX3 ENST00000219746.14

TSL:2MANE Select

HGVSc / HGVSpc.88-31681A>G

Exon rankIntron 1 of 6

intron

Prot: ENSP00000219746.9UniProt: O15405-1

TOX3 ENST00000912163.1

HGVSc / HGVSpc.88-31681A>G

Exon rankIntron 1 of 7

intron

Prot: ENSP00000582222.1UniProt: A0ACI8SKH9

TOX3 ENST00000873102.1

HGVSc / HGVSpc.88-31681A>G

Exon rankIntron 1 of 6

intron

Prot: ENSP00000543161.1UniProt: A0ACI8R9S9

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.608	AC:92442	Hom:28642	AN:151924	Cov:32
GnomAD4 genome	AF: 0.608	AC:92509	Hom:28673	AN:152040	Cov:32
TOPMed (Bravo)	AF: 0.614	AC:162397	Hom:50587	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.579	AC:188548	Hom:55109	AN:325382	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.629	AC:1472	Hom:470	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.821	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.533	AC:160	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.730	AC:2539	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.795	AC:5753	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.494	AC:87	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.790	AC:96992	Hom:38425	AN:122792	Cov:
Turkish Variome	AF: 0.607	AC:938	Hom:279	AN:1546	Cov:
UK10K	AF: 0.555	AC:4197	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.824	AC:7386	Hom:3068	AN:8960	Cov:

Showing 14 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	2.4
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.55
DANN	Benign	0.35
GPN-Star LLR	N/A	2.1
GPN-Star score	N/A	-2.1
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-0.57

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs8051542;

hg19: chr16-52534167;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar