rs3219463

Variant names:

• chr1-45340760-C-T
• rs3219463
• NM_025077.4:c.53-313C>T

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 -14 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Moderate

The NM_025077.4(TOE1):c.53-313C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.27 (AC=41,025) in the gnomAD database across 151,990 control chromosomes, including 5,839 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.394. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

• Frequency: Genomes: 𝑓 0.27 (5839 hom., cov: 31)
• Consequence: TOE1 NM_025077.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.367
• Publications: 14 publications found

Genes affected

TOE1 (HGNC:15954): (target of EGR1, exonuclease) Enables poly(A)-specific ribonuclease activity and snRNA binding activity. Involved in snRNA 3'-end processing. Located in Cajal body and cytoplasm. Implicated in pontocerebellar hypoplasia type 7. [provided by Alliance of Genome Resources, Jul 2025]

TOE1 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 7

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia

ENSG00000288208 (HGNC:):

MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]

MUTYH Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• colorectal cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AR, AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -14 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).
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.3941 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_025077.4. 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
	TOE1 NM_025077.4	MANE Select	c.53-313C>T	intron	Intron 1 of 7	Prot: NP_079353.3

TOE1 NM_025077.4

MANE Select

HGVSc / HGVSpc.53-313C>T

Exon rankIntron 1 of 7

intron

Prot: NP_079353.3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TOE1 ENST00000372090.6	TSL:1MANE Select	c.53-313C>T	intron	Intron 1 of 7	Prot: ENSP00000361162.5 UniProt:
	ENSG00000288208 ENST00000671898.1		n.541-6249G>A	intron	Intron 5 of 20	Prot: ENSP00000499896.1 UniProt:
	TOE1 ENST00000874144.1		c.71-313C>T	intron	Intron 1 of 7	Prot: ENSP00000544203.1 UniProt:

TOE1 ENST00000372090.6

TSL:1MANE Select

HGVSc / HGVSpc.53-313C>T

Exon rankIntron 1 of 7

intron

Prot: ENSP00000361162.5UniProt: Q96GM8-1

ENSG00000288208 ENST00000671898.1

HGVSc / HGVSpn.541-6249G>A

Exon rankIntron 5 of 20

intron

Prot: ENSP00000499896.1UniProt: A0A5F9ZGZ0

TOE1 ENST00000874144.1

HGVSc / HGVSpc.71-313C>T

Exon rankIntron 1 of 7

intron

Prot: ENSP00000544203.1UniProt: A0ACI8QUQ1

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: 0.270	AC:40947	Hom:5808	AN:151872	Cov:31
GnomAD4 genome	AF: 0.270	AC:41025	Hom:5839	AN:151990	Cov:31
TOPMed (Bravo)	AF: 0.288	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.252	AC:10022	Hom:1328	AN:39740	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.306	AC:717	Hom:116	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.316	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.193	AC:58	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.344	AC:1194	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.322	AC:2326	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.375	AC:66	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.359	AC:44014	Hom:7924	AN:122638	Cov:
Turkish Variome	AF: 0.237	AC:366	Hom:39	AN:1542	Cov:
UK10K	AF: 0.251	AC:1895	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.332	AC:2979	Hom:479	AN:8960	Cov:

Showing 14 sources

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	8.0
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.6
DANN	Benign	0.68
GPN-Star LLR	N/A	-1.2
GPN-Star score	N/A	1.2
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	0.37
PromoterAI	N/A	-0.023	Neutral

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.010	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: rs3219463;

hg19: chr1-45806432;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar