chr1-45332662-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001048174.2(MUTYH):ā€‹c.518T>Cā€‹(p.Met173Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M173V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

5
12
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 8.89
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.745

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MUTYHNM_001048174.2 linkc.518T>C p.Met173Thr missense_variant 8/16 ENST00000456914.7 NP_001041639.1 Q9UIF7-6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MUTYHENST00000456914.7 linkc.518T>C p.Met173Thr missense_variant 8/161 NM_001048174.2 ENSP00000407590.2 Q9UIF7-6
ENSG00000288208ENST00000671898.1 linkn.1106T>C non_coding_transcript_exon_variant 12/21 ENSP00000499896.1 A0A5F9ZGZ0

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461870
Hom.:
0
Cov.:
36
AF XY:
0.00
AC XY:
0
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 21, 2022- -
Familial adenomatous polyposis 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 26, 2024This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 201 of the MUTYH protein (p.Met201Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 464733). 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 disruptive. 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 13, 2024The p.M201T variant (also known as c.602T>C), located in coding exon 8 of the MUTYH gene, results from a T to C substitution at nucleotide position 602. The methionine at codon 201 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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
Uncertain
0.56
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.010
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.33
.;.;.;.;.;T;.;.;.;T;.;T
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
.;D;.;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.75
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.72
D
MutationAssessor
Uncertain
2.0
.;.;.;.;.;M;.;.;.;.;.;.
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-3.5
D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.69
Sift
Uncertain
0.0070
D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.015
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.68, 0.63, 0.68
.;.;.;.;.;P;P;.;P;.;.;.
Vest4
0.70
MutPred
0.60
.;.;.;.;.;.;.;.;Gain of disorder (P = 0.0562);.;.;.;
MVP
0.95
MPC
0.50
ClinPred
0.93
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.85
gMVP
0.77

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553128600; hg19: chr1-45798334; API