dbSNP rs2308321: MGMT:p.Ile143Val (chr10-129766800-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002412.5(MGMT):c.427A>G(p.Ile143Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,612,120 control chromosomes in the GnomAD database, including 12,315 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.087 ( 829 hom., cov: 34)

Exomes 𝑓: 0.12 ( 11486 hom. )

Consequence

MGMT
NM_002412.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.66

Publications

124 publications found

Variant links:

Genes affected

MGMT (HGNC:7059): (O-6-methylguanine-DNA methyltransferase) Alkylating agents are potent carcinogens that can result in cell death, mutation and cancer. The protein encoded by this gene is a DNA repair protein that is involved in cellular defense against mutagenesis and toxicity from alkylating agents. The protein catalyzes transfer of methyl groups from O(6)-alkylguanine and other methylated moieties of the DNA to its own molecule, which repairs the toxic lesions. Methylation of the genes promoter has been associated with several cancer types, including colorectal cancer, lung cancer, lymphoma and glioblastoma. [provided by RefSeq, Sep 2015]

MGMT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030550957).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5 link	c.427A>G	p.Ile143Val	missense_variant	Exon 5 of 5	ENST00000651593.1	NP_002403.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1 link	c.427A>G	p.Ile143Val	missense_variant	Exon 5 of 5		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8 link	c.520A>G	p.Ile174Val	missense_variant	Exon 5 of 5	1		ENSP00000302111.7

Frequencies

GnomAD3 genomes

AF:

0.0872

AC:

13276

AN:

152182

Hom.:

830

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0225

Gnomad AMI

AF:

0.195

Gnomad AMR

AF:

0.0719

Gnomad ASJ

AF:

0.0761

Gnomad EAS

AF:

0.0118

Gnomad SAS

AF:

0.0750

Gnomad FIN

AF:

0.130

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.0871

GnomAD2 exomes

AF:

0.0927

AC:

22954

AN:

247730

AF XY:

0.0970

show subpopulations

Gnomad AFR exome

AF:

0.0188

Gnomad AMR exome

AF:

0.0471

Gnomad ASJ exome

AF:

0.0877

Gnomad EAS exome

AF:

0.00885

Gnomad FIN exome

AF:

0.122

Gnomad NFE exome

AF:

0.129

Gnomad OTH exome

AF:

0.0986

GnomAD4 exome

AF:

0.120

AC:

174673

AN:

1459820

Hom.:

11486

Cov.:

AF XY:

0.119

AC XY:

86520

AN XY:

726216

show subpopulations

African (AFR)

AF:

0.0180

AC:

601

AN:

33456

American (AMR)

AF:

0.0492

AC:

2197

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.0883

AC:

2303

AN:

26096

East Asian (EAS)

AF:

0.00496

AC:

197

AN:

39694

South Asian (SAS)

AF:

0.0830

AC:

7154

AN:

86142

European-Finnish (FIN)

AF:

0.120

AC:

6339

AN:

52634

Middle Eastern (MID)

AF:

0.0888

AC:

496

AN:

5588

European-Non Finnish (NFE)

AF:

0.134

AC:

149006

AN:

1111262

Other (OTH)

AF:

0.106

AC:

6380

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

7365

14730

22095

29460

36825

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5240

10480

15720

20960

26200

<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:

0.0871

AC:

13272

AN:

152300

Hom.:

829

Cov.:

AF XY:

0.0858

AC XY:

6393

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0224

AC:

931

AN:

41578

American (AMR)

AF:

0.0718

AC:

1099

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0761

AC:

264

AN:

3470

East Asian (EAS)

AF:

0.0116

AC:

AN:

5166

South Asian (SAS)

AF:

0.0757

AC:

365

AN:

4824

European-Finnish (FIN)

AF:

0.130

AC:

1380

AN:

10620

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.129

AC:

8774

AN:

68012

Other (OTH)

AF:

0.0871

AC:

184

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

632

1264

1897

2529

3161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

158

316

474

632

790

<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:

0.116

Hom.:

4288

Bravo

AF:

0.0799

TwinsUK

AF:

0.143

AC:

531

ALSPAC

AF:

0.129

AC:

497

ESP6500AA

AF:

0.0225

AC:

ESP6500EA

AF:

0.128

AC:

1104

ExAC

AF:

0.0921

AC:

11173

Asia WGS

AF:

0.0380

AC:

133

AN:

3478

EpiCase

AF:

0.133

EpiControl

AF:

0.127

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.72

CADD

Benign

8.7

(source)

DANN

Benign

0.55

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.86

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0031

MetaSVM

Benign

-0.91

PhyloP100

1.7

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.12

REVEL

Benign

0.051

Sift

Benign

0.51

Sift4G

Benign

0.47

Vest4

0.11

MPC

0.062

ClinPred

0.00077

GERP RS

-0.42

gMVP

0.43

Mutation Taster

=97/3

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over