rs1553137063

chr1-45340241-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000372098.7(MUTYH):c.14T>C(p.Val5Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V5I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MUTYH ENST00000372098.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.103

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06525937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.14T>C	p.Val5Ala	missense_variant	1/16	ENST00000710952.2
TOE1	NM_025077.4	c.-12A>G		5_prime_UTR_variant	1/8	ENST00000372090.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.14T>C	p.Val5Ala	missense_variant	1/16		NM_001128425.2
TOE1	ENST00000372090.6	c.-12A>G		5_prime_UTR_variant	1/8	1	NM_025077.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461472 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

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

Mar 11, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 533299). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 5 of the MUTYH protein (p.Val5Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	11
Dann	Benign	0.71
DEOGEN2	Benign	0.046	T;.;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.41	T;T;T;T;T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.065	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.080	N;N;N;N;N
REVEL	Benign	0.0040
Sift	Benign	0.13	T;T;T;T;D
Sift4G	Benign	0.59	T;T;T;T;D
Polyphen		0.0	B;B;.;B;.
Vest4		0.081
MutPred		0.27		Gain of disorder (P = 0.0452);Gain of disorder (P = 0.0452);Gain of disorder (P = 0.0452);Gain of disorder (P = 0.0452);Gain of disorder (P = 0.0452);
MVP		0.20
MPC		0.14
ClinPred		0.053	T
GERP RS		-1.3
Varity_R		0.031
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1553137063; hg19: chr1-45805913;