chr1-45340209-T-G

Variant names:

• chr1-45340209-T-G
• rs201746729
• NM_025077.4:c.-44T>G

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Supporting

The NM_025077.4(TOE1):c.-44T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000753 (AC=11) in the gnomAD database across 1,461,392 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000335. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TOE1 NM_025077.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.253
• Publications: 0 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

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

ENSG00000288208 (HGNC:):

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000033 — very rare (O3 supporting [+1])

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.-44T>G	5_prime_UTR	Exon 1 of 8	Prot: NP_079353.3
	MUTYH NM_001128425.2	MANE Plus Clinical	c.36+10A>C	intron	Intron 1 of 15	Prot: NP_001121897.1 UniProt:
	MUTYH NM_001407071.1		c.-13A>C	5_prime_UTR	Exon 1 of 16	Prot: NP_001394000.1 UniProt:

TOE1 NM_025077.4

MANE Select

HGVSc / HGVSpc.-44T>G

Exon rankExon 1 of 8

5_prime_UTR

Prot: NP_079353.3

MUTYH NM_001128425.2

MANE Plus Clinical

HGVSc / HGVSpc.36+10A>C

Exon rankIntron 1 of 15

intron

Prot: NP_001121897.1UniProt: E5KP25

MUTYH NM_001407071.1

HGVSc / HGVSpc.-13A>C

Exon rankExon 1 of 16

5_prime_UTR

Prot: NP_001394000.1UniProt: Q9UIF7-5E5KP28

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TOE1 ENST00000372090.6	TSL:1MANE Select	c.-44T>G	5_prime_UTR	Exon 1 of 8	Prot: ENSP00000361162.5 UniProt:
	MUTYH ENST00000710952.2	MANE Plus Clinical	c.36+10A>C	intron	Intron 1 of 15	Prot: ENSP00000518552.2 UniProt:
	MUTYH ENST00000372098.7	TSL:1	c.36+10A>C	intron	Intron 1 of 15	Prot: ENSP00000361170.3 UniProt:

TOE1 ENST00000372090.6

TSL:1MANE Select

HGVSc / HGVSpc.-44T>G

Exon rankExon 1 of 8

5_prime_UTR

Prot: ENSP00000361162.5UniProt: Q96GM8-1

MUTYH ENST00000710952.2

MANE Plus Clinical

HGVSc / HGVSpc.36+10A>C

Exon rankIntron 1 of 15

intron

Prot: ENSP00000518552.2UniProt: E5KP25

MUTYH ENST00000372098.7

TSL:1

HGVSc / HGVSpc.36+10A>C

Exon rankIntron 1 of 15

intron

Prot: ENSP00000361170.3UniProt: Q9UIF7-1

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:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000401	AC:1	Hom:	AN:249128	Cov:
GnomAD4 exome	AF: 0.00000753	AC:11	Hom:0	AN:1461392	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000820	AC:10	Hom:0	AN:121448	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000296	2	67606	0.00000753	1	132806

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Familial adenomatous polyposis 2 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	18
AlphaMissense	Uncertain	0.42
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.4
DANN	Benign	0.74
GPN-Star LLR	N/A	-2.1
GPN-Star score	N/A	2.1
PhyloP100	Benign	-0.25
PromoterAI	N/A	0.046	Neutral

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.080
SpliceAI score (max)	Benign	0.030	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: rs201746729;

hg19: chr1-45805881;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar