Variant rs36053993 details in Genebe, Genetics Data Aggregator

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

Splicing: ADA: 0.9998

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.51

Links

MUTYH (HGNC:7527):

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
MUTYH	NM_001048174.2 linkuse as main transcript	c.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
MUTYH	ENST00000456914.7 linkuse as main transcript	c.1103G>T	p.Gly368Val	missense_variant, splice_region_variant	13/16	1	NM_001048174.2	P4	Q9UIF7-6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461596

Hom.:

AF XY:

0.00

AC XY:

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 submitter

clinical testing

Invitae

Feb 20, 2022

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). 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

BayesDel_noAF

Pathogenic

0.53

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

1.0

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.50

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.71

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Links

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over