rs4750759

Variant names:

• chr10-129638339-G-A
• rs4750759
• NM_002412.5:c.126-69556G>A

Variant summary

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

The NM_002412.5(MGMT):​c.126-69556G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 149,592 control chromosomes in the GnomAD database, including 22,246 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 0.54 (22246 hom., cov: 27)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.146
• Publications: 12 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.126-69556G>A		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.126-69556G>A		intron_variant	Intron 2 of 4		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.219-69556G>A		intron_variant	Intron 2 of 4	1		ENSP00000302111.7

Frequencies

GnomAD3 genomes AF: 0.545 AC: 81393 AN: 149466 Hom.: 22215 Cov.: 27

Gnomad AFR AF: 0.605

Gnomad AMI AF: 0.517

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.616

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.530

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

GnomAD4 genome AF: 0.545 AC: 81475 AN: 149592 Hom.: 22246 Cov.: 27 AF XY: 0.548 AC XY: 39923 AN XY: 72872

African (AFR) AF: 0.605 AC: 24682 AN: 40818

American (AMR) AF: 0.544 AC: 8153 AN: 14988

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1713 AN: 3448

East Asian (EAS) AF: 0.391 AC: 1915 AN: 4894

South Asian (SAS) AF: 0.460 AC: 2129 AN: 4632

European-Finnish (FIN) AF: 0.616 AC: 6229 AN: 10106

Middle Eastern (MID) AF: 0.521 AC: 149 AN: 286

European-Non Finnish (NFE) AF: 0.518 AC: 34946 AN: 67446

Other (OTH) AF: 0.528 AC: 1092 AN: 2070

Alfa AF: 0.523 Hom.: 10457

Bravo AF: 0.540

Asia WGS AF: 0.437 AC: 1520 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.96
DANN	Benign	0.50
PhyloP100		-0.15
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: rs4750759; hg19: chr10-131436603;