rs16906252

Variant names:

• chr10-129467281-C-T
• rs16906252
• ENST00000306010.8:c.66C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 BA1

The NM_002412.5(MGMT):​c.-28C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0635 in 1,543,640 control chromosomes in the GnomAD database, including 3,472 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 0.050 (298 hom., cov: 33)
  • Exomes 𝑓: 0.065 (3174 hom.)
• Consequence: MGMT NM_002412.5 5_prime_UTR
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.412
• Publications: 78 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]

ENSG00000296036 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.-28C>T		5_prime_UTR_variant	Exon 1 of 5	ENST00000651593.1	NP_002403.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.-28C>T		5_prime_UTR_variant	Exon 1 of 5		NM_002412.5	ENSP00000498729.1

Frequencies

GnomAD3 genomes AF: 0.0503 AC: 7658 AN: 152154 Hom.: 298 Cov.: 33

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.0369

Gnomad ASJ AF: 0.0703

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0366

Gnomad FIN AF: 0.0870

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0746

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0555 AC: 8097 AN: 145974 AF XY: 0.0564

Gnomad AFR exome AF: 0.00904

Gnomad AMR exome AF: 0.0320

Gnomad ASJ exome AF: 0.0714

Gnomad EAS exome AF: 0.000104

Gnomad FIN exome AF: 0.0851

Gnomad NFE exome AF: 0.0740

Gnomad OTH exome AF: 0.0643

GnomAD4 exome AF: 0.0650 AC: 90419 AN: 1391368 Hom.: 3174 Cov.: 39 AF XY: 0.0649 AC XY: 44581 AN XY: 686666

African (AFR) AF: 0.00972 AC: 299 AN: 30772

American (AMR) AF: 0.0340 AC: 1184 AN: 34820

Ashkenazi Jewish (ASJ) AF: 0.0733 AC: 1828 AN: 24938

East Asian (EAS) AF: 0.000145 AC: 5 AN: 34538

South Asian (SAS) AF: 0.0419 AC: 3289 AN: 78554

European-Finnish (FIN) AF: 0.0895 AC: 4227 AN: 47230

Middle Eastern (MID) AF: 0.0537 AC: 304 AN: 5666

European-Non Finnish (NFE) AF: 0.0706 AC: 76042 AN: 1077118

Other (OTH) AF: 0.0561 AC: 3241 AN: 57732

GnomAD4 genome AF: 0.0503 AC: 7660 AN: 152272 Hom.: 298 Cov.: 33 AF XY: 0.0509 AC XY: 3790 AN XY: 74446

African (AFR) AF: 0.0108 AC: 450 AN: 41576

American (AMR) AF: 0.0370 AC: 566 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0703 AC: 244 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0370 AC: 179 AN: 4832

European-Finnish (FIN) AF: 0.0870 AC: 922 AN: 10596

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0746 AC: 5070 AN: 67984

Other (OTH) AF: 0.0374 AC: 79 AN: 2114

Alfa AF: 0.0634 Hom.: 154

Bravo AF: 0.0444

Asia WGS AF: 0.0190 AC: 67 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Glioblastoma Other:1

Mar 10, 2016

Database of Curated Mutations (DoCM)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Benign	0.96
PhyloP100		0.41
PromoterAI		0.31	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.79		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs16906252; hg19: chr10-131265545; COSMIC: COSV60026712;