10-129627758-T-C

Variant names:

• chr10-129627758-T-C
• rs477692
• NM_002412.5:c.126-80137T>C

Variant summary

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

The NM_002412.5(MGMT):​c.126-80137T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 152,146 control chromosomes in the GnomAD database, including 16,020 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 0.45 (16020 hom., cov: 34)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• Publications: 29 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002412.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MGMT	NM_002412.5	MANE Select	c.126-80137T>C		intron	N/A	NP_002403.3	P16455

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MGMT	ENST00000651593.1	MANE Select	c.126-80137T>C		intron	N/A	ENSP00000498729.1	P16455
	MGMT	ENST00000306010.8	TSL:1	c.219-80137T>C		intron	N/A	ENSP00000302111.7	B4DEE8
	MGMT	ENST00000897068.1		c.126-80137T>C		intron	N/A	ENSP00000567127.1

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68814 AN: 152028 Hom.: 16012 Cov.: 34

Gnomad AFR AF: 0.358

Gnomad AMI AF: 0.440

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.623

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.492

Gnomad OTH AF: 0.474

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.453 AC: 68851 AN: 152146 Hom.: 16020 Cov.: 34 AF XY: 0.450 AC XY: 33503 AN XY: 74378

African (AFR) AF: 0.358 AC: 14870 AN: 41494

American (AMR) AF: 0.458 AC: 7000 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1737 AN: 3470

East Asian (EAS) AF: 0.623 AC: 3225 AN: 5174

South Asian (SAS) AF: 0.552 AC: 2659 AN: 4818

European-Finnish (FIN) AF: 0.408 AC: 4322 AN: 10582

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.492 AC: 33484 AN: 68006

Other (OTH) AF: 0.476 AC: 1007 AN: 2114

Alfa AF: 0.484 Hom.: 71515

Bravo AF: 0.452

Asia WGS AF: 0.555 AC: 1930 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.3
DANN	Benign	0.59
PhyloP100		1.1
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: rs477692; hg19: chr10-131426022;