NM_025077.4:c.-50C>G

Variant names:

• chr1-45340203-C-G
• rs748512468
• NM_025077.4:c.-50C>G

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_ModerateBP6_Moderate

The NM_025077.4(TOE1):c.-50C>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 0.000000684 (AC=1) in the gnomAD database across 1,461,268 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. 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: 6.8e-7 (0 hom.)
• Consequence: TOE1 NM_025077.4 5_prime_UTR
• Scores: Splicing: ADA: 0.03721
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.26
• 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

Our verdict: Likely_benign. The variant received -2 points.

• PM2: Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AR gene (threshold 0.001) — PM2 moderate.
• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
• BP6: ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 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.-50C>G		5_prime_UTR	Exon 1 of 8	NP_079353.3
	MUTYH	NM_001128425.2	MANE Plus Clinical	c.36+16G>C		intron	N/A	NP_001121897.1	E5KP25
	MUTYH	NM_001407071.1		c.-7G>C		splice_region	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.-50C>G		5_prime_UTR	Exon 1 of 8	ENSP00000361162.5	Q96GM8-1
	MUTYH	ENST00000710952.2	MANE Plus Clinical	c.36+16G>C		intron	N/A	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000372098.7	TSL:1	c.36+16G>C		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 6 sources Large-scale international reference populations
GnomAD3 genomes					32
GnomAD2 exomes	0.00000402	1		248788
GnomAD4 exome	6.84e-7	1	0	1461268	33
GnomAD4 genome					32
TOPMed (Bravo)	0.00000378	1	0	264690
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.00	0	0	13470

Showing 6 sources

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Familial adenomatous polyposis 2 (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	25
AlphaMissense	Uncertain	-	0.35
BayesDel_noAF	Benign	-	-0.39
CADD	Benign	-	18
DANN	Benign	-	0.86
GPN-Star LLR	N/A	-	-3.0
GPN-Star score	N/A	-	3.0
PhyloP100	Benign	-	1.3
PromoterAI	N/A	Neutral	-0.029

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
dbscSNV1_ADA	Benign	-	0.037
dbscSNV1_RF	Benign	-	0.27
Pangolin (max)	Benign	-	0.020
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 4 of 4 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: rs748512468;

hg19: chr1-45805875;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar