10-129622012-C-T

Position:

• chr10-129622012-C-T

Variant summary

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

The NM_002412.5(MGMT):​c.125+85635C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 152,070 control chromosomes in the GnomAD database, including 20,040 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 0.51 (20040 hom., cov: 33)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.879

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MGMT	NM_002412.5	c.125+85635C>T		intron_variant		ENST00000651593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MGMT	ENST00000651593.1	c.125+85635C>T		intron_variant			NM_002412.5	P1
MGMT	ENST00000306010.8	c.218+85635C>T		intron_variant		1
	ENST00000662900.1	n.2954G>A		non_coding_transcript_exon_variant	4/4

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77298 AN: 151952 Hom.: 20009 Cov.: 33

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.563

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.376

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.472

Gnomad OTH AF: 0.484

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

GnomAD4 genome AF: 0.509 AC: 77378 AN: 152070 Hom.: 20040 Cov.: 33 AF XY: 0.511 AC XY: 37989 AN XY: 74332

Gnomad4 AFR AF: 0.590

Gnomad4 AMR AF: 0.502

Gnomad4 ASJ AF: 0.481

Gnomad4 EAS AF: 0.376

Gnomad4 SAS AF: 0.388

Gnomad4 FIN AF: 0.568

Gnomad4 NFE AF: 0.472

Gnomad4 OTH AF: 0.481

Alfa AF: 0.495 Hom.: 3821

Bravo AF: 0.509

Asia WGS AF: 0.404 AC: 1404 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	1.1
DANN	Benign	0.47

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: rs7091540; hg19: chr10-131420276;