Genetic Variant NM_001128425.2:c.1153G>A (chr1-45331694-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001128425.2(MUTYH):c.1153G>A(p.Ala385Thr) 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. 16/22 in silico tools predict a benign 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. A385P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

MUTYH
NM_001128425.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.93

Publications

3 publications found

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]

MUTYH Gene-Disease associations (from GenCC):

familial adenomatous polyposis 2
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
colorectal cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
familial ovarian cancer
Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

MUTYH links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 47 uncertain in NM_001128425.2

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13359901).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128425.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MUTYH	NM_001128425.2	MANE Plus Clinical	c.1153G>A	p.Ala385Thr	missense	Exon 12 of 16	NP_001121897.1
MUTYH	NM_001048174.2	MANE Select	c.1069G>A	p.Ala357Thr	missense	Exon 12 of 16	NP_001041639.1
MUTYH	NM_012222.3		c.1144G>A	p.Ala382Thr	missense	Exon 12 of 16	NP_036354.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MUTYH	ENST00000710952.2	MANE Plus Clinical	c.1153G>A	p.Ala385Thr	missense	Exon 12 of 16	ENSP00000518552.2
MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.1069G>A	p.Ala357Thr	missense	Exon 12 of 16	ENSP00000407590.2
MUTYH	ENST00000372098.7	TSL:1	c.1144G>A	p.Ala382Thr	missense	Exon 12 of 16	ENSP00000361170.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial adenomatous polyposis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

0.0047

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.059

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.048

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.55

M_CAP

Benign

0.084

MetaRNN

Benign

0.13

MetaSVM

Uncertain

0.33

MutationAssessor

Benign

0.23

PhyloP100

1.9

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.33

REVEL

Benign

0.28

Sift

Benign

0.43

Sift4G

Benign

0.48

Polyphen

0.0010

Vest4

0.052

MutPred

0.41

Loss of stability (P = 0.1463)

MVP

0.93

MPC

0.11

ClinPred

0.19

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.084

gMVP

0.31

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over