rs7075748

Positions:

• chr10-129758408-T-C

Variant summary

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

The NM_002412.5(MGMT):​c.275-794T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 151,828 control chromosomes in the GnomAD database, including 8,497 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 0.33 (8497 hom., cov: 32)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36

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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MGMT	NM_002412.5	c.275-794T>C		intron_variant		ENST00000651593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MGMT	ENST00000651593.1	c.275-794T>C		intron_variant			NM_002412.5	P1
MGMT	ENST00000306010.8	c.368-794T>C		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49360 AN: 151710 Hom.: 8469 Cov.: 32

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.552

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.309

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

GnomAD4 genome AF: 0.325 AC: 49419 AN: 151828 Hom.: 8497 Cov.: 32 AF XY: 0.335 AC XY: 24858 AN XY: 74200

Gnomad4 AFR AF: 0.279

Gnomad4 AMR AF: 0.433

Gnomad4 ASJ AF: 0.387

Gnomad4 EAS AF: 0.553

Gnomad4 SAS AF: 0.409

Gnomad4 FIN AF: 0.388

Gnomad4 NFE AF: 0.295

Gnomad4 OTH AF: 0.310

Alfa AF: 0.313 Hom.: 1251

Bravo AF: 0.325

Asia WGS AF: 0.477 AC: 1657 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	0.082
DANN	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs7075748; hg19: chr10-131556672;