10-129691134-G-A

Position:

• chr10-129691134-G-A

Variant summary

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

The NM_002412.5(MGMT):​c.126-16761G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 152,198 control chromosomes in the GnomAD database, including 2,571 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 0.17 (2571 hom., cov: 33)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.46

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGMT	NM_002412.5	c.126-16761G>A		intron_variant		ENST00000651593.1	NP_002403.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.126-16761G>A		intron_variant			NM_002412.5	ENSP00000498729	P1
MGMT	ENST00000306010.8	c.219-16761G>A		intron_variant		1		ENSP00000302111

Frequencies

GnomAD3 genomes AF: 0.171 AC: 26024 AN: 152080 Hom.: 2573 Cov.: 33

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.169

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

GnomAD4 genome AF: 0.171 AC: 26031 AN: 152198 Hom.: 2571 Cov.: 33 AF XY: 0.172 AC XY: 12811 AN XY: 74418

Gnomad4 AFR AF: 0.244

Gnomad4 AMR AF: 0.122

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.349

Gnomad4 SAS AF: 0.206

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.168

Alfa AF: 0.156 Hom.: 261

Bravo AF: 0.173

Asia WGS AF: 0.240 AC: 833 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.15
DANN	Benign	0.65

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: rs11016878; hg19: chr10-131489398;