rs4751109

chr10-129680564-C-A

Variant summary

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

The NM_002412.5(MGMT):c.126-27331C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 140,430 control chromosomes in the GnomAD database, including 1,150 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 0.12 (1150 hom., cov: 32)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.301

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 (NFE) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MGMT	NM_002412.5	c.126-27331C>A		intron_variant		ENST00000651593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MGMT	ENST00000651593.1	c.126-27331C>A		intron_variant			NM_002412.5	P1
MGMT	ENST00000306010.8	c.219-27331C>A		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 16509 AN: 140326 Hom.: 1151 Cov.: 32

Gnomad AFR AF: 0.0350

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.0909

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.112

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

GnomAD4 genome AF: 0.118 AC: 16512 AN: 140430 Hom.: 1150 Cov.: 32 AF XY: 0.116 AC XY: 8006 AN XY: 68724

Gnomad4 AFR AF: 0.0349

Gnomad4 AMR AF: 0.147

Gnomad4 ASJ AF: 0.150

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.0924

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.165

Gnomad4 OTH AF: 0.113

Alfa AF: 0.129 Hom.: 243

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	2.5
Dann	Benign	0.34

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: rs4751109; hg19: chr10-131478828;