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GeneBe

rs12917

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002412.5(MGMT):c.250C>T(p.Leu84Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,612,866 control chromosomes in the GnomAD database, including 14,557 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.14 ( 1559 hom., cov: 32)
Exomes 𝑓: 0.13 ( 12998 hom. )

Consequence

MGMT
NM_002412.5 missense

Scores

16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.06
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0018567145).
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MGMTNM_002412.5 linkuse as main transcriptc.250C>T p.Leu84Phe missense_variant 3/5 ENST00000651593.1
LOC105378560XR_946467.3 linkuse as main transcript upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MGMTENST00000651593.1 linkuse as main transcriptc.250C>T p.Leu84Phe missense_variant 3/5 NM_002412.5 P1
MGMTENST00000306010.8 linkuse as main transcriptc.343C>T p.Leu115Phe missense_variant 3/51
MGMTENST00000462672.1 linkuse as main transcriptn.411C>T non_coding_transcript_exon_variant 2/43

Frequencies

GnomAD3 genomes
AF:
0.139
AC:
21094
AN:
152030
Hom.:
1547
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.147
Gnomad AMI
AF:
0.0625
Gnomad AMR
AF:
0.192
Gnomad ASJ
AF:
0.121
Gnomad EAS
AF:
0.108
Gnomad SAS
AF:
0.139
Gnomad FIN
AF:
0.112
Gnomad MID
AF:
0.123
Gnomad NFE
AF:
0.130
Gnomad OTH
AF:
0.146
GnomAD3 exomes
AF:
0.144
AC:
36058
AN:
250342
Hom.:
2865
AF XY:
0.141
AC XY:
19011
AN XY:
135290
show subpopulations
Gnomad AFR exome
AF:
0.149
Gnomad AMR exome
AF:
0.232
Gnomad ASJ exome
AF:
0.137
Gnomad EAS exome
AF:
0.0968
Gnomad SAS exome
AF:
0.144
Gnomad FIN exome
AF:
0.112
Gnomad NFE exome
AF:
0.131
Gnomad OTH exome
AF:
0.140
GnomAD4 exome
AF:
0.131
AC:
190678
AN:
1460718
Hom.:
12998
Cov.:
32
AF XY:
0.131
AC XY:
94923
AN XY:
726658
show subpopulations
Gnomad4 AFR exome
AF:
0.157
Gnomad4 AMR exome
AF:
0.224
Gnomad4 ASJ exome
AF:
0.137
Gnomad4 EAS exome
AF:
0.125
Gnomad4 SAS exome
AF:
0.143
Gnomad4 FIN exome
AF:
0.109
Gnomad4 NFE exome
AF:
0.126
Gnomad4 OTH exome
AF:
0.133
GnomAD4 genome
AF:
0.139
AC:
21135
AN:
152148
Hom.:
1559
Cov.:
32
AF XY:
0.141
AC XY:
10455
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.147
Gnomad4 AMR
AF:
0.193
Gnomad4 ASJ
AF:
0.121
Gnomad4 EAS
AF:
0.109
Gnomad4 SAS
AF:
0.139
Gnomad4 FIN
AF:
0.112
Gnomad4 NFE
AF:
0.130
Gnomad4 OTH
AF:
0.146
Alfa
AF:
0.132
Hom.:
3149
Bravo
AF:
0.144
TwinsUK
AF:
0.128
AC:
474
ALSPAC
AF:
0.119
AC:
460
ESP6500AA
AF:
0.150
AC:
660
ESP6500EA
AF:
0.127
AC:
1092
ExAC
AF:
0.142
AC:
17209
Asia WGS
AF:
0.115
AC:
398
AN:
3478
EpiCase
AF:
0.133
EpiControl
AF:
0.130

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.75
T
BayesDel_noAF
Benign
-0.70
Cadd
Benign
8.6
Dann
Benign
0.96
Eigen
Benign
-0.46
Eigen_PC
Benign
-0.53
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.62
T
MetaRNN
Benign
0.0019
T
MetaSVM
Benign
-0.96
T
MutationTaster
Benign
0.0089
P
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-0.61
N
REVEL
Benign
0.053
Sift
Benign
0.27
T
Sift4G
Benign
0.42
T
Vest4
0.071
MPC
0.064
ClinPred
0.0051
T
GERP RS
1.9
gMVP
0.42

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs12917; hg19: chr10-131506283; COSMIC: COSV60031127; API