rs12917

Positions:

• chr10-129708019-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/18 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06

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

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	Protein	UniProt
MGMT	NM_002412.5	c.250C>T	p.Leu84Phe	missense_variant	3/5	ENST00000651593.1	NP_002403.3
LOC105378560	XR_946467.3			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.250C>T	p.Leu84Phe	missense_variant	3/5		NM_002412.5	ENSP00000498729	P1
MGMT	ENST00000306010.8	c.343C>T	p.Leu115Phe	missense_variant	3/5	1		ENSP00000302111
MGMT	ENST00000462672.1	n.411C>T		non_coding_transcript_exon_variant	2/4	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

GnomAD3 exomes AF: 0.144 AC: 36058 AN: 250342 Hom.: 2865 AF XY: 0.141 AC XY: 19011 AN XY: 135290

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

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

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

Other links and lift over

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