rs12247354

Variant names:

• chr10-129638297-A-G
• rs12247354
• NM_002412.5:c.126-69598A>G

Variant summary

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

The NM_002412.5(MGMT):​c.126-69598A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 151,604 control chromosomes in the GnomAD database, including 7,164 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 0.30 (7164 hom., cov: 31)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.212
• Publications: 15 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.126-69598A>G		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.126-69598A>G		intron_variant	Intron 2 of 4		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.219-69598A>G		intron_variant	Intron 2 of 4	1		ENSP00000302111.7

Frequencies

GnomAD3 genomes AF: 0.303 AC: 45922 AN: 151486 Hom.: 7150 Cov.: 31

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.0498

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.289

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

GnomAD4 genome AF: 0.303 AC: 45967 AN: 151604 Hom.: 7164 Cov.: 31 AF XY: 0.300 AC XY: 22206 AN XY: 74050

African (AFR) AF: 0.322 AC: 13300 AN: 41322

American (AMR) AF: 0.301 AC: 4579 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1026 AN: 3470

East Asian (EAS) AF: 0.0497 AC: 257 AN: 5168

South Asian (SAS) AF: 0.182 AC: 872 AN: 4796

European-Finnish (FIN) AF: 0.348 AC: 3649 AN: 10496

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.313 AC: 21199 AN: 67830

Other (OTH) AF: 0.286 AC: 602 AN: 2102

Alfa AF: 0.310 Hom.: 4118

Bravo AF: 0.303

Asia WGS AF: 0.123 AC: 428 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.0
DANN	Benign	0.73
PhyloP100		-0.21
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: rs12247354; hg19: chr10-131436561;