10-129702676-G-C

Position:

• chr10-129702676-G-C

Variant summary

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

The NM_002412.5(MGMT):​c.126-5219G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 152,074 control chromosomes in the GnomAD database, including 11,781 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 0.38 (11781 hom., cov: 33)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.740

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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGMT	NM_002412.5	c.126-5219G>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.126-5219G>C		intron_variant			NM_002412.5	ENSP00000498729	P1
MGMT	ENST00000306010.8	c.219-5219G>C		intron_variant		1		ENSP00000302111
MGMT	ENST00000462672.1	n.286+764G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57650 AN: 151954 Hom.: 11785 Cov.: 33

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.365

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

GnomAD4 genome AF: 0.379 AC: 57668 AN: 152074 Hom.: 11781 Cov.: 33 AF XY: 0.379 AC XY: 28142 AN XY: 74328

Gnomad4 AFR AF: 0.240

Gnomad4 AMR AF: 0.326

Gnomad4 ASJ AF: 0.418

Gnomad4 EAS AF: 0.338

Gnomad4 SAS AF: 0.409

Gnomad4 FIN AF: 0.499

Gnomad4 NFE AF: 0.455

Gnomad4 OTH AF: 0.368

Alfa AF: 0.419 Hom.: 1767

Bravo AF: 0.359

Asia WGS AF: 0.350 AC: 1217 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.7
DANN	Benign	0.69

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: rs11016883; hg19: chr10-131500940;