10-129716206-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.274+8163C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 152,104 control chromosomes in the GnomAD database, including 8,866 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 0.30 (8866 hom., cov: 33)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.332

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]

LOC105378560 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MGMT	NM_002412.5	c.274+8163C>T		intron_variant		ENST00000651593.1
LOC105378560	XR_946467.3	n.7555+602C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MGMT	ENST00000651593.1	c.274+8163C>T		intron_variant			NM_002412.5	P1
MGMT	ENST00000306010.8	c.367+8163C>T		intron_variant		1
MGMT	ENST00000462672.1	n.520+602C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46122 AN: 151986 Hom.: 8834 Cov.: 33

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.479

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.305

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

GnomAD4 genome AF: 0.304 AC: 46212 AN: 152104 Hom.: 8866 Cov.: 33 AF XY: 0.310 AC XY: 23026 AN XY: 74364

Gnomad4 AFR AF: 0.526

Gnomad4 AMR AF: 0.271

Gnomad4 ASJ AF: 0.253

Gnomad4 EAS AF: 0.479

Gnomad4 SAS AF: 0.269

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.176

Gnomad4 OTH AF: 0.311

Alfa AF: 0.224 Hom.: 2041

Bravo AF: 0.315

Asia WGS AF: 0.419 AC: 1456 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.28
Dann	Benign	0.74

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: rs11016887; hg19: chr10-131514470;