1-45340253-A-T

Position:

• chr1-45340253-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_025077.4(TOE1):​c.1A>T​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TOE1 NM_025077.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36

Genes affected

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.2T>A	p.Met1?	start_lost	1/16	ENST00000710952.2
TOE1	NM_025077.4	c.1A>T	p.Met1?	start_lost	1/8	ENST00000372090.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.2T>A	p.Met1?	start_lost	1/16		NM_001128425.2
TOE1	ENST00000372090.6	c.1A>T	p.Met1?	start_lost	1/8	1	NM_025077.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 28, 2020

This sequence change affects the initiator methionine of the MUTYH mRNA. The next in-frame methionine is located at codon 15. This variant at the initiator codon is expected to affect translation initiation. However, there are alternative transcripts using downstream Met15 as an initiator codon that can potentially re-initiate the translation. Rescue of the translation may result in the N-terminal truncation missing mitochondrial localization signal (MLS) (residues 1-14), but the role of MLS is not well understood (PMID: 20725929). Therefore, it is uncertain whether this variant results in an absent or disrupted protein product. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with MUTYH-related conditions. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.034	T;.;.;.;.
Eigen	Benign	-0.061
Eigen_PC	Benign	0.033
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N;N;N;N;N;D;D
PROVEAN	Benign	0.36	N;N;N;N;N
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.048	D;T;T;D;T
Polyphen		0.81	P;P;.;P;.
Vest4		0.84
MutPred		1.0		Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);
MVP		0.56
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.94
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs865954220; hg19: chr1-45805925;