rs11016884

Variant names:

• chr10-129706231-T-C
• rs11016884
• NM_002412.5:c.126-1664T>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.126-1664T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 152,138 control chromosomes in the GnomAD database, including 7,902 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 0.32 (7902 hom., cov: 33)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.288
• Publications: 5 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.126-1664T>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.126-1664T>C		intron_variant	Intron 2 of 4		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.219-1664T>C		intron_variant	Intron 2 of 4	1		ENSP00000302111.7
MGMT	ENST00000462672.1	n.287-1664T>C		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48340 AN: 152020 Hom.: 7899 Cov.: 33

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.347

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.341

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

GnomAD4 genome AF: 0.318 AC: 48358 AN: 152138 Hom.: 7902 Cov.: 33 AF XY: 0.318 AC XY: 23639 AN XY: 74378

African (AFR) AF: 0.333 AC: 13802 AN: 41496

American (AMR) AF: 0.367 AC: 5615 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1023 AN: 3470

East Asian (EAS) AF: 0.318 AC: 1642 AN: 5158

South Asian (SAS) AF: 0.349 AC: 1683 AN: 4822

European-Finnish (FIN) AF: 0.236 AC: 2499 AN: 10600

Middle Eastern (MID) AF: 0.346 AC: 101 AN: 292

European-Non Finnish (NFE) AF: 0.311 AC: 21131 AN: 67978

Other (OTH) AF: 0.337 AC: 712 AN: 2110

Alfa AF: 0.322 Hom.: 11409

Bravo AF: 0.325

Asia WGS AF: 0.327 AC: 1133 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.45
PhyloP100		-0.29
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: rs11016884; hg19: chr10-131504495;