10-129654653-C-T

Variant names:

• chr10-129654653-C-T
• rs4750761
• NM_002412.5:c.126-53242C>T

Variant summary

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

The NM_002412.5(MGMT):​c.126-53242C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 151,612 control chromosomes in the GnomAD database, including 9,561 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 0.34 (9561 hom., cov: 31)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.40
• Publications: 6 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.126-53242C>T		intron_variant	Intron 2 of 4	ENST00000651593.1	NP_002403.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.126-53242C>T		intron_variant	Intron 2 of 4		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.219-53242C>T		intron_variant	Intron 2 of 4	1		ENSP00000302111.7

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51828 AN: 151494 Hom.: 9544 Cov.: 31

Gnomad AFR AF: 0.463

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.0483

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.309

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.314

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

GnomAD4 genome AF: 0.342 AC: 51875 AN: 151612 Hom.: 9561 Cov.: 31 AF XY: 0.340 AC XY: 25205 AN XY: 74036

African (AFR) AF: 0.463 AC: 19114 AN: 41304

American (AMR) AF: 0.305 AC: 4656 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1034 AN: 3466

East Asian (EAS) AF: 0.0482 AC: 246 AN: 5106

South Asian (SAS) AF: 0.174 AC: 833 AN: 4786

European-Finnish (FIN) AF: 0.405 AC: 4249 AN: 10504

Middle Eastern (MID) AF: 0.312 AC: 91 AN: 292

European-Non Finnish (NFE) AF: 0.303 AC: 20572 AN: 67894

Other (OTH) AF: 0.311 AC: 655 AN: 2108

Alfa AF: 0.310 Hom.: 10776

Bravo AF: 0.342

Asia WGS AF: 0.128 AC: 447 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.078
DANN	Benign	0.51
PhyloP100		-2.4
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: rs4750761; hg19: chr10-131452917;