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rs36053993

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_001048174.2(MUTYH):c.1103G>T(p.Gly368Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. 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. G368D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense, splice_region

Scores

12
3
1
Splicing: ADA: 0.9998
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.51
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 Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001048174.2
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-45331556-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MUTYHNM_001128425.2 linkuse as main transcriptc.1187G>T p.Gly396Val missense_variant, splice_region_variant 13/16 ENST00000710952.2
MUTYHNM_001048174.2 linkuse as main transcriptc.1103G>T p.Gly368Val missense_variant, splice_region_variant 13/16 ENST00000456914.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MUTYHENST00000710952.2 linkuse as main transcriptc.1187G>T p.Gly396Val missense_variant, splice_region_variant 13/16 NM_001128425.2
MUTYHENST00000456914.7 linkuse as main transcriptc.1103G>T p.Gly368Val missense_variant, splice_region_variant 13/161 NM_001048174.2 A1Q9UIF7-6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461596
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727082
show subpopulations
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 19, 2023In 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 variant disrupts the p.Gly396 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11818965, 16557584, 17489848, 19793053). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 645786). 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 glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 396 of the MUTYH protein (p.Gly396Val). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.53
Cadd
Pathogenic
34
Dann
Uncertain
1.0
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
1.0
D
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.50
D
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-6.1
D;D;D;D;D;D;D;D;D;D;D;.
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0, 1.0
.;.;.;.;.;.;D;D;.;.;D;.
Vest4
0.86
MutPred
0.84
.;.;.;.;.;.;.;.;.;.;Loss of glycosylation at S395 (P = 0.0662);.;
MVP
1.0
MPC
0.62
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.99
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.24
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.24
Position offset: -12

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: rs36053993; hg19: chr1-45797228; API