rs150792276

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The NM_001048174.2(MUTYH):c.1192C>T(p.Arg398Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,614,058 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R398H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00080 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:16B:10

Conservation

PhyloP100: 0.702

Publications

39 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: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet
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: AR, AD Classification: NO_KNOWN Submitted by: ClinGen

MUTYH links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 16 benign, 56 uncertain in NM_001048174.2

BP4

Computational evidence support a benign effect (MetaRNN=0.05789399).

BP6

Variant 1-45331467-G-A is Benign according to our data. Variant chr1-45331467-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41753.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001048174.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MUTYH	NM_001128425.2	MANE Plus Clinical	c.1276C>T	p.Arg426Cys	missense	Exon 13 of 16	NP_001121897.1	E5KP25
MUTYH	NM_001048174.2	MANE Select	c.1192C>T	p.Arg398Cys	missense	Exon 13 of 16	NP_001041639.1	Q9UIF7-6
MUTYH	NM_012222.3		c.1267C>T	p.Arg423Cys	missense	Exon 13 of 16	NP_036354.1	Q9UIF7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MUTYH	ENST00000710952.2	MANE Plus Clinical	c.1276C>T	p.Arg426Cys	missense	Exon 13 of 16	ENSP00000518552.2	E5KP25
MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.1192C>T	p.Arg398Cys	missense	Exon 13 of 16	ENSP00000407590.2	Q9UIF7-6
MUTYH	ENST00000372098.7	TSL:1	c.1267C>T	p.Arg423Cys	missense	Exon 13 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00141

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000816

AC:

205

AN:

251232

AF XY:

0.000861

show subpopulations

Gnomad AFR exome

AF:

0.000555

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000979

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00142

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00136

AC:

1990

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

953

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33480

American (AMR)

AF:

0.000268

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.000403

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000937

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00168

AC:

1871

AN:

1112008

Other (OTH)

AF:

0.00124

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

134

268

401

535

669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

156

234

312

390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000802

AC:

122

AN:

152208

Hom.:

Cov.:

AF XY:

0.000713

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41456

American (AMR)

AF:

0.000589

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000385

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00141

AC:

AN:

68038

Other (OTH)

AF:

0.000956

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00129

Hom.:

Bravo

AF:

0.000861

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000774

AC:

EpiCase

AF:

0.00147

EpiControl

AF:

0.00190

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Familial adenomatous polyposis 2 (6)

Hereditary cancer-predisposing syndrome (5)

not specified (4)

Carcinoma of colon (2)

Hereditary cancer (1)

MUTYH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.54

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.74

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.058

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.5

PhyloP100

0.70

PrimateAI

Benign

0.26

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.61

Sift

Benign

0.036

Sift4G

Uncertain

0.042

Polyphen

0.0010

Vest4

0.22

MVP

0.86

MPC

0.15

ClinPred

0.56

GERP RS

1.8

Varity_R

0.18

gMVP

0.38

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over