10-129712029-T-C

Variant names:

• chr10-129712029-T-C
• rs4751115
• NM_002412.5:c.274+3986T>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.274+3986T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 152,096 control chromosomes in the GnomAD database, including 24,827 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 0.56 (24827 hom., cov: 33)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.729 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.274+3986T>C		intron	N/A	NP_002403.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MGMT	ENST00000651593.1	MANE Select	c.274+3986T>C		intron	N/A	ENSP00000498729.1
	MGMT	ENST00000306010.8	TSL:1	c.367+3986T>C		intron	N/A	ENSP00000302111.7
	MGMT	ENST00000897068.1		c.274+3986T>C		intron	N/A	ENSP00000567127.1

Frequencies

GnomAD3 genomes AF: 0.558 AC: 84797 AN: 151978 Hom.: 24787 Cov.: 33

Gnomad AFR AF: 0.736

Gnomad AMI AF: 0.317

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.476

Gnomad OTH AF: 0.533

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

GnomAD4 genome AF: 0.558 AC: 84889 AN: 152096 Hom.: 24827 Cov.: 33 AF XY: 0.557 AC XY: 41413 AN XY: 74364

African (AFR) AF: 0.736 AC: 30542 AN: 41500

American (AMR) AF: 0.545 AC: 8337 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1448 AN: 3472

East Asian (EAS) AF: 0.648 AC: 3351 AN: 5168

South Asian (SAS) AF: 0.534 AC: 2574 AN: 4822

European-Finnish (FIN) AF: 0.449 AC: 4739 AN: 10558

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.476 AC: 32332 AN: 67966

Other (OTH) AF: 0.537 AC: 1132 AN: 2108

Alfa AF: 0.501 Hom.: 33594

Bravo AF: 0.570

Asia WGS AF: 0.617 AC: 2142 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.79
DANN	Benign	0.46
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4751115; hg19: chr10-131510293;