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rs36053993

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2_SupportingPM5PP3_Moderate

The NM_001048174.2(MUTYH):c.1103G>T(p.Gly368Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD Genomes project. 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)

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

Links

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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; Number of alleles below threshold, Median coverage is 33.
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_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
MUTYHENST00000456914.7 linkuse as main transcriptc.1103G>T p.Gly368Val missense_variant, splice_region_variant 13/161 NM_001048174.2 P4Q9UIF7-6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461596
Hom.:
0
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

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 testingInvitaeFeb 20, 2022This 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). 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: 645786). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. 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. -

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
32
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;