rs3858300

Positions:

• chr10-129543865-A-C
• chr10-129543865-A-G
• chr10-129543865-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002412.5(MGMT):​c.125+7488A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 152,010 control chromosomes in the GnomAD database, including 35,312 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 0.68 (35312 hom., cov: 32)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.980

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGMT	NM_002412.5	c.125+7488A>C		intron_variant		ENST00000651593.1	NP_002403.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.125+7488A>C		intron_variant			NM_002412.5	ENSP00000498729	P1
MGMT	ENST00000306010.8	c.218+7488A>C		intron_variant		1		ENSP00000302111
MGMT	ENST00000482653.1	n.205+7488A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.677 AC: 102807 AN: 151892 Hom.: 35289 Cov.: 32

Gnomad AFR AF: 0.737

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.687

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.954

Gnomad SAS AF: 0.746

Gnomad FIN AF: 0.618

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.685

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

GnomAD4 genome AF: 0.677 AC: 102878 AN: 152010 Hom.: 35312 Cov.: 32 AF XY: 0.679 AC XY: 50438 AN XY: 74282

Gnomad4 AFR AF: 0.737

Gnomad4 AMR AF: 0.687

Gnomad4 ASJ AF: 0.673

Gnomad4 EAS AF: 0.954

Gnomad4 SAS AF: 0.745

Gnomad4 FIN AF: 0.618

Gnomad4 NFE AF: 0.623

Gnomad4 OTH AF: 0.686

Alfa AF: 0.641 Hom.: 14992

Bravo AF: 0.685

Asia WGS AF: 0.842 AC: 2928 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.5
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3858300; hg19: chr10-131342129; COSMIC: COSV60022562;