10-129548200-T-C

Variant names:

• chr10-129548200-T-C
• rs4751099
• NM_002412.5:c.125+11823T>C

Variant summary

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

The NM_002412.5(MGMT):​c.125+11823T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 152,198 control chromosomes in the GnomAD database, including 4,787 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 0.23 (4787 hom., cov: 33)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.150
• Publications: 14 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.302 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.125+11823T>C		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.125+11823T>C		intron_variant	Intron 2 of 4		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.218+11823T>C		intron_variant	Intron 2 of 4	1		ENSP00000302111.7
MGMT	ENST00000482653.1	n.205+11823T>C		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35294 AN: 152080 Hom.: 4784 Cov.: 33

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.0402

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.222

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

GnomAD4 genome AF: 0.232 AC: 35314 AN: 152198 Hom.: 4787 Cov.: 33 AF XY: 0.230 AC XY: 17095 AN XY: 74398

African (AFR) AF: 0.115 AC: 4771 AN: 41544

American (AMR) AF: 0.241 AC: 3679 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 914 AN: 3472

East Asian (EAS) AF: 0.0403 AC: 209 AN: 5186

South Asian (SAS) AF: 0.172 AC: 828 AN: 4824

European-Finnish (FIN) AF: 0.310 AC: 3278 AN: 10584

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20744 AN: 67992

Other (OTH) AF: 0.221 AC: 466 AN: 2112

Alfa AF: 0.282 Hom.: 3592

Bravo AF: 0.223

Asia WGS AF: 0.0960 AC: 335 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.32
DANN	Benign	0.70
PhyloP100		-0.15
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: rs4751099; hg19: chr10-131346464;