chr10-129628693-T-G

Variant names:

• chr10-129628693-T-G
• rs558764
• NM_002412.5:c.126-79202T>G

Variant summary

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

The NM_002412.5(MGMT):​c.126-79202T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 152,028 control chromosomes in the GnomAD database, including 14,218 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 0.42 (14218 hom., cov: 33)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0690
• Publications: 9 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.126-79202T>G		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.126-79202T>G		intron_variant	Intron 2 of 4		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.219-79202T>G		intron_variant	Intron 2 of 4	1		ENSP00000302111.7

Frequencies

GnomAD3 genomes AF: 0.419 AC: 63617 AN: 151910 Hom.: 14216 Cov.: 33

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.623

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.448

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

GnomAD4 genome AF: 0.419 AC: 63630 AN: 152028 Hom.: 14218 Cov.: 33 AF XY: 0.417 AC XY: 31005 AN XY: 74282

African (AFR) AF: 0.260 AC: 10766 AN: 41474

American (AMR) AF: 0.446 AC: 6811 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1726 AN: 3472

East Asian (EAS) AF: 0.623 AC: 3218 AN: 5162

South Asian (SAS) AF: 0.552 AC: 2661 AN: 4820

European-Finnish (FIN) AF: 0.393 AC: 4149 AN: 10560

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.483 AC: 32809 AN: 67946

Other (OTH) AF: 0.450 AC: 950 AN: 2110

Alfa AF: 0.435 Hom.: 2625

Bravo AF: 0.416

Asia WGS AF: 0.550 AC: 1912 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.3
DANN	Benign	0.53
PhyloP100		-0.069
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: rs558764; hg19: chr10-131426957;