10-129707928-C-T

Variant names:

• chr10-129707928-C-T
• rs1803965
• NM_002412.5:c.159C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002412.5(MGMT):​c.159C>T​(p.Leu53Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,612,080 control chromosomes in the GnomAD database, including 12,582 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1547 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11035 hom.)
• Consequence: MGMT NM_002412.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.314
• Publications: 37 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP7: Synonymous conserved (PhyloP=-0.314 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.159C>T	p.Leu53Leu	synonymous_variant	Exon 3 of 5	ENST00000651593.1	NP_002403.3
LOC105378560	XR_946467.3	n.-122C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.159C>T	p.Leu53Leu	synonymous_variant	Exon 3 of 5		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.252C>T	p.Leu84Leu	synonymous_variant	Exon 3 of 5	1		ENSP00000302111.7
MGMT	ENST00000462672.1	n.320C>T		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20336 AN: 151906 Hom.: 1534 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.142

GnomAD2 exomes AF: 0.133 AC: 33222 AN: 250436 AF XY: 0.129

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.228

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.0956

Gnomad FIN exome AF: 0.0460

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.118 AC: 172611 AN: 1460056 Hom.: 11035 Cov.: 32 AF XY: 0.119 AC XY: 86105 AN XY: 726336

African (AFR) AF: 0.182 AC: 6093 AN: 33474

American (AMR) AF: 0.221 AC: 9894 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3488 AN: 26136

East Asian (EAS) AF: 0.125 AC: 4954 AN: 39700

South Asian (SAS) AF: 0.139 AC: 11996 AN: 86248

European-Finnish (FIN) AF: 0.0475 AC: 2460 AN: 51750

Middle Eastern (MID) AF: 0.132 AC: 748 AN: 5686

European-Non Finnish (NFE) AF: 0.113 AC: 125444 AN: 1111966

Other (OTH) AF: 0.125 AC: 7534 AN: 60374

GnomAD4 genome AF: 0.134 AC: 20380 AN: 152024 Hom.: 1547 Cov.: 32 AF XY: 0.133 AC XY: 9873 AN XY: 74302

African (AFR) AF: 0.172 AC: 7120 AN: 41428

American (AMR) AF: 0.192 AC: 2928 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 410 AN: 3470

East Asian (EAS) AF: 0.106 AC: 546 AN: 5152

South Asian (SAS) AF: 0.136 AC: 650 AN: 4796

European-Finnish (FIN) AF: 0.0395 AC: 419 AN: 10608

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7917 AN: 67984

Other (OTH) AF: 0.142 AC: 300 AN: 2108

Alfa AF: 0.127 Hom.: 2404

Bravo AF: 0.145

Asia WGS AF: 0.113 AC: 393 AN: 3478

EpiCase AF: 0.124

EpiControl AF: 0.120

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.1
DANN	Benign	0.59
PhyloP100		-0.31
Mutation Taster		=100/0	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: rs1803965; hg19: chr10-131506192; COSMIC: COSV60032343;