NM_025077.4:c.-44T>C

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-7 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -7 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4_StrongBP6_Strong

The NM_025077.4(TOE1):c.-44T>C 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 0.00000248 (AC=4) in the gnomAD database across 1,613,674 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000193. In-silico predictor (AlphaMissense) 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TOE1 NM_025077.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 RNA phosphodiester bond hydrolysis, exonucleolytic and snRNA 3'-end processing. Located in Cajal body and cytoplasm. Implicated in pontocerebellar hypoplasia type 7. [provided by Alliance of Genome Resources, Apr 2022]

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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -7 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000193 — borderline rare for AR gene (threshold 0.001) — PM2 supporting.
	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 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

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>C		5_prime_UTR	Exon 1 of 8	NP_079353.3
	MUTYH	NM_001128425.2	MANE Plus Clinical	c.36+10A>G		intron	N/A	NP_001121897.1	E5KP25
	MUTYH	NM_001407071.1		c.-13A>G		5_prime_UTR	Exon 1 of 16	NP_001394000.1	Q9UIF7-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOE1	ENST00000372090.6	TSL:1 MANE Select	c.-44T>C		5_prime_UTR	Exon 1 of 8	ENSP00000361162.5	Q96GM8-1
	MUTYH	ENST00000710952.2	MANE Plus Clinical	c.36+10A>G		intron	N/A	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000372098.7	TSL:1	c.36+10A>G		intron	N/A	ENSP00000361170.3	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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152164	Cov:32
GnomAD4 exome	AF: 0.00000205	AC:3	Hom:0	AN:1461392	Cov:33
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152282	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13470	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.000478	AC:58	Hom:0	AN:121448	Cov:

Showing 6 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	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	17
AlphaMissense	Benign	0.25
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.0
DANN	Benign	0.73
GPN-Star LLR	N/A	-2.0
GPN-Star score	N/A	2.0
PhyloP100	Benign	-0.25
PromoterAI	N/A	0.084	Neutral

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.12
Pangolin gain	Benign	0.12	Position offset: 10
SpliceAI score (max)	Benign	0.050	Details are displayed if max score is > 0.2

Showing 3 of 3 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.

Other links and lift over

dbSNP: rs201746729;

hg19: chr1-45805881;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar