1-45333568-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001128425.2(MUTYH):​c.193C>A​(p.Pro65Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P65S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MUTYH
NM_001128425.2 missense

Scores

2
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.54
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in NM_001128425.2
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12102389).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MUTYHNM_001048174.2 linkuse as main transcriptc.116-7C>A splice_region_variant, intron_variant ENST00000456914.7 NP_001041639.1 Q9UIF7-6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MUTYHENST00000456914.7 linkuse as main transcriptc.116-7C>A splice_region_variant, intron_variant 1 NM_001048174.2 ENSP00000407590.2 Q9UIF7-6
ENSG00000288208ENST00000671898.1 linkuse as main transcriptn.697C>A non_coding_transcript_exon_variant 7/21 ENSP00000499896.1 A0A5F9ZGZ0

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
7.6
DANN
Benign
0.95
DEOGEN2
Benign
0.061
.;T;.;T;T
Eigen
Benign
-0.86
Eigen_PC
Benign
-0.88
FATHMM_MKL
Benign
0.32
N
LIST_S2
Benign
0.54
T;T;T;T;T
M_CAP
Benign
0.0087
T
MetaRNN
Benign
0.12
T;T;T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.97
.;L;.;.;.
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.1
N;N;N;N;N
REVEL
Benign
0.038
Sift
Uncertain
0.019
D;D;D;T;D
Sift4G
Uncertain
0.046
D;T;D;T;T
Polyphen
0.19
.;B;B;.;.
Vest4
0.25
MutPred
0.48
.;.;Gain of helix (P = 0.027);.;.;
MVP
0.56
MPC
0.13
ClinPred
0.11
T
GERP RS
1.4
Varity_R
0.036
gMVP
0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-45799240; API