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

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_001080430.4(TOX3):c.88-31681A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The gene TOX3 is a tumor suppressor gene (CancerMine: 2 TSG citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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: not found (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 ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

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>C	intron	Intron 1 of 6	Prot: NP_001073899.2 UniProt:
	TOX3 NM_001146188.2		c.75+19151A>C	intron	Intron 2 of 7	Prot: NP_001139660.1 UniProt:

TOX3 NM_001080430.4

MANE Select

HGVSc / HGVSpc.88-31681A>C

Exon rankIntron 1 of 6

intron

Prot: NP_001073899.2UniProt: O15405-1

TOX3 NM_001146188.2

HGVSc / HGVSpc.75+19151A>C

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>C	intron	Intron 1 of 6	Prot: ENSP00000219746.9 UniProt:
	TOX3 ENST00000912163.1		c.88-31681A>C	intron	Intron 1 of 7	Prot: ENSP00000582222.1 UniProt:
	TOX3 ENST00000873102.1		c.88-31681A>C	intron	Intron 1 of 6	Prot: ENSP00000543161.1 UniProt:

TOX3 ENST00000219746.14

TSL:2MANE Select

HGVSc / HGVSpc.88-31681A>C

Exon rankIntron 1 of 6

intron

Prot: ENSP00000219746.9UniProt: O15405-1

TOX3 ENST00000912163.1

HGVSc / HGVSpc.88-31681A>C

Exon rankIntron 1 of 7

intron

Prot: ENSP00000582222.1UniProt: A0ACI8SKH9

TOX3 ENST00000873102.1

HGVSc / HGVSpc.88-31681A>C

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	2.3
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.47
DANN	Benign	0.39
GPN-Star LLR	N/A	4.5
GPN-Star score	N/A	0.052
PhyloP100	Benign	-0.57

Showing 7 of 7 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