rs12917

Variant names:

• chr10-129708019-C-T
• rs12917
• NM_002412.5:c.250C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 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 0.14 (1559 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12998 hom.)
• Consequence: MGMT NM_002412.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06
• Publications: 181 publications found

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]

LOC105378560 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.250C>T	p.Leu84Phe	missense_variant	Exon 3 of 5	ENST00000651593.1	NP_002403.3
LOC105378560	XR_946467.3	n.-31C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.250C>T	p.Leu84Phe	missense_variant	Exon 3 of 5		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.343C>T	p.Leu115Phe	missense_variant	Exon 3 of 5	1		ENSP00000302111.7
MGMT	ENST00000462672.1	n.411C>T		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21094 AN: 152030 Hom.: 1547 Cov.: 32

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

GnomAD2 exomes AF: 0.144 AC: 36058 AN: 250342 AF XY: 0.141

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 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

African (AFR) AF: 0.157 AC: 5229 AN: 33394

American (AMR) AF: 0.224 AC: 9987 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3568 AN: 26064

East Asian (EAS) AF: 0.125 AC: 4977 AN: 39686

South Asian (SAS) AF: 0.143 AC: 12315 AN: 86218

European-Finnish (FIN) AF: 0.109 AC: 5782 AN: 53244

Middle Eastern (MID) AF: 0.131 AC: 755 AN: 5752

European-Non Finnish (NFE) AF: 0.126 AC: 140017 AN: 1111532

Other (OTH) AF: 0.133 AC: 8048 AN: 60330

GnomAD4 genome AF: 0.139 AC: 21135 AN: 152148 Hom.: 1559 Cov.: 32 AF XY: 0.141 AC XY: 10455 AN XY: 74388

African (AFR) AF: 0.147 AC: 6113 AN: 41494

American (AMR) AF: 0.193 AC: 2943 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 421 AN: 3472

East Asian (EAS) AF: 0.109 AC: 562 AN: 5168

South Asian (SAS) AF: 0.139 AC: 666 AN: 4808

European-Finnish (FIN) AF: 0.112 AC: 1193 AN: 10606

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8837 AN: 68002

Other (OTH) AF: 0.146 AC: 308 AN: 2114

Alfa AF: 0.134 Hom.: 6017

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
PhyloP100		1.1
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
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

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