10-129601352-G-T

Variant names:

• chr10-129601352-G-T
• rs3852507
• NM_002412.5:c.125+64975G>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.125+64975G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 151,914 control chromosomes in the GnomAD database, including 21,359 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 0.53 (21359 hom., cov: 32)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.523
• Publications: 10 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.613 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.125+64975G>T		intron_variant	Intron 2 of 4	ENST00000651593.1	NP_002403.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.125+64975G>T		intron_variant	Intron 2 of 4		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.218+64975G>T		intron_variant	Intron 2 of 4	1		ENSP00000302111.7

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79696 AN: 151798 Hom.: 21333 Cov.: 32

Gnomad AFR AF: 0.620

Gnomad AMI AF: 0.570

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.363

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.491

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

GnomAD4 genome AF: 0.525 AC: 79764 AN: 151914 Hom.: 21359 Cov.: 32 AF XY: 0.523 AC XY: 38805 AN XY: 74240

African (AFR) AF: 0.619 AC: 25648 AN: 41424

American (AMR) AF: 0.508 AC: 7753 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 1696 AN: 3466

East Asian (EAS) AF: 0.363 AC: 1867 AN: 5144

South Asian (SAS) AF: 0.402 AC: 1936 AN: 4820

European-Finnish (FIN) AF: 0.534 AC: 5632 AN: 10540

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.494 AC: 33545 AN: 67940

Other (OTH) AF: 0.490 AC: 1032 AN: 2106

Alfa AF: 0.502 Hom.: 19804

Bravo AF: 0.528

Asia WGS AF: 0.402 AC: 1397 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.44
PhyloP100		-0.52
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: rs3852507; hg19: chr10-131399616;