rs12269324

Variant names:

• chr10-129468206-T-A
• rs12269324
• NM_002412.5:c.-13+910T>A

Variant summary

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

The NM_002412.5(MGMT):​c.-13+910T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 152,092 control chromosomes in the GnomAD database, including 3,833 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 0.22 (3833 hom., cov: 32)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.252
• Publications: 7 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.-13+910T>A		intron_variant	Intron 1 of 4	ENST00000651593.1	NP_002403.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.-13+910T>A		intron_variant	Intron 1 of 4		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.81+910T>A		intron_variant	Intron 1 of 4	1		ENSP00000302111.7
MGMT	ENST00000482547.1	n.35+910T>A		intron_variant	Intron 1 of 1	2
MGMT	ENST00000482653.1	n.68+910T>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32717 AN: 151974 Hom.: 3823 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.0368

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.192

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

GnomAD4 genome AF: 0.215 AC: 32760 AN: 152092 Hom.: 3833 Cov.: 32 AF XY: 0.215 AC XY: 15972 AN XY: 74342

African (AFR) AF: 0.161 AC: 6699 AN: 41490

American (AMR) AF: 0.219 AC: 3353 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 809 AN: 3472

East Asian (EAS) AF: 0.0369 AC: 191 AN: 5176

South Asian (SAS) AF: 0.180 AC: 868 AN: 4810

European-Finnish (FIN) AF: 0.264 AC: 2789 AN: 10572

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.253 AC: 17225 AN: 67978

Other (OTH) AF: 0.190 AC: 402 AN: 2114

Alfa AF: 0.234 Hom.: 567

Bravo AF: 0.209

Asia WGS AF: 0.114 AC: 395 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.74
DANN	Benign	0.51
PhyloP100		-0.25
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: rs12269324; hg19: chr10-131266470;