rs4751104

Positions:

• chr10-129607094-G-A

Variant summary

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

The NM_002412.5(MGMT):​c.125+70717G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 151,982 control chromosomes in the GnomAD database, including 13,310 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 0.41 (13310 hom., cov: 32)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.118

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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MGMT	NM_002412.5	c.125+70717G>A		intron_variant		ENST00000651593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MGMT	ENST00000651593.1	c.125+70717G>A		intron_variant			NM_002412.5	P1
MGMT	ENST00000306010.8	c.218+70717G>A		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61947 AN: 151864 Hom.: 13294 Cov.: 32

Gnomad AFR AF: 0.507

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.0625

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.386

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

GnomAD4 genome AF: 0.408 AC: 62000 AN: 151982 Hom.: 13310 Cov.: 32 AF XY: 0.406 AC XY: 30165 AN XY: 74254

Gnomad4 AFR AF: 0.507

Gnomad4 AMR AF: 0.395

Gnomad4 ASJ AF: 0.404

Gnomad4 EAS AF: 0.0621

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.476

Gnomad4 NFE AF: 0.379

Gnomad4 OTH AF: 0.384

Alfa AF: 0.382 Hom.: 5266

Bravo AF: 0.409

Asia WGS AF: 0.165 AC: 577 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.39
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs4751104; hg19: chr10-131405358;