1-45331237-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001048174.2(MUTYH):​c.1337G>C​(p.Arg446Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,210 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R446C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

MUTYH
NM_001048174.2 missense

Scores

6
11
2

Clinical Significance

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

Conservation

PhyloP100: 4.40
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MUTYHNM_001048174.2 linkc.1337G>C p.Arg446Pro missense_variant Exon 14 of 16 ENST00000456914.7 NP_001041639.1 Q9UIF7-6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MUTYHENST00000456914.7 linkc.1337G>C p.Arg446Pro missense_variant Exon 14 of 16 1 NM_001048174.2 ENSP00000407590.2 Q9UIF7-6
ENSG00000288208ENST00000671898.1 linkn.1925G>C non_coding_transcript_exon_variant Exon 18 of 21 ENSP00000499896.1 A0A5F9ZGZ0

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152210
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
32
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152210
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2
Apr 04, 2019
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 16, 2015
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R474P variant (also known as c.1421G>C), located in coding exon 14 of the MUTYH gene, results from a G to C substitution at nucleotide position 1421. The arginine at codon 474 is replaced by proline, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 75,000 alleles tested) in our clinical cohort.This amino acid position is well 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 p.R474P remains unclear. -

Familial adenomatous polyposis 2 Uncertain:1
Sep 26, 2018
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 sequence change replaces arginine with proline at codon 474 of the MUTYH protein (p.Arg474Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 232935). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.79
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.70
.;.;.;.;.;.;D;.;.;.;.;D
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
.;.;D;.;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.35
D
MutationAssessor
Uncertain
2.6
.;.;.;.;.;.;M;.;.;.;.;.
PrimateAI
Benign
0.36
T
PROVEAN
Uncertain
-4.1
D;D;D;D;D;D;D;D;D;D;D;.
REVEL
Uncertain
0.61
Sift
Uncertain
0.0020
D;D;D;D;D;D;D;D;D;D;D;.
Sift4G
Uncertain
0.0060
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.99, 1.0, 1.0
.;.;.;.;.;.;D;D;.;.;D;.
Vest4
0.93
MutPred
0.80
.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at W475 (P = 0.0116);.;
MVP
0.89
MPC
0.65
ClinPred
0.98
D
GERP RS
5.2
Varity_R
0.98
gMVP
0.87

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: rs764276907; hg19: chr1-45796909; API