1-45340226-C-T

Position:

• chr1-45340226-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000372090.6(TOE1):​c.-27C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TOE1 ENST00000372090.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.382

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08058402).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.29G>A	p.Arg10His	missense_variant	1/16	ENST00000710952.2	NP_001121897.1
TOE1	NM_025077.4	c.-27C>T		5_prime_UTR_variant	1/8	ENST00000372090.6	NP_079353.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.29G>A	p.Arg10His	missense_variant	1/16		NM_001128425.2	ENSP00000518552
TOE1	ENST00000372090.6	c.-27C>T		5_prime_UTR_variant	1/8	1	NM_025077.4	ENSP00000361162	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 249550 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135424

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461482 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727058

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 02, 2023	This missense variant replaces arginine with histidine at codon 10 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 6/249550 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 27, 2023	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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 464709). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is present in population databases (rs755928199, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 10 of the MUTYH protein (p.Arg10His). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 10, 2021

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2024

The p.R10H variant (also known as c.29G>A), located in coding exon 1 of the MUTYH gene, results from a G to A substitution at nucleotide position 29. The arginine at codon 10 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.043	T;.;.;.;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.63	T;T;T;T;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.081	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.040	N;N;N;N;N
REVEL	Benign	0.053
Sift	Uncertain	0.020	D;D;D;D;T
Sift4G	Benign	0.14	T;T;T;T;D
Polyphen		0.70	P;P;.;P;.
Vest4		0.19
MutPred		0.28		Loss of disorder (P = 0.0496);Loss of disorder (P = 0.0496);Loss of disorder (P = 0.0496);Loss of disorder (P = 0.0496);Loss of disorder (P = 0.0496);
MVP		0.38
MPC		0.19
ClinPred		0.23	T
GERP RS		0.47
Varity_R		0.044
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs755928199; hg19: chr1-45805898;