rs551491

Variant names:

• chr10-129599557-G-A
• rs551491
• NM_002412.5:c.125+63180G>A

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+63180G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 151,990 control chromosomes in the GnomAD database, including 15,089 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 0.43 (15089 hom., cov: 32)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.30
• 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.125+63180G>A		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+63180G>A		intron_variant	Intron 2 of 4		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.218+63180G>A		intron_variant	Intron 2 of 4	1		ENSP00000302111.7

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65091 AN: 151872 Hom.: 15090 Cov.: 32

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.636

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.496

Gnomad OTH AF: 0.471

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

GnomAD4 genome AF: 0.428 AC: 65099 AN: 151990 Hom.: 15089 Cov.: 32 AF XY: 0.431 AC XY: 32006 AN XY: 74250

African (AFR) AF: 0.241 AC: 9978 AN: 41440

American (AMR) AF: 0.475 AC: 7250 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1758 AN: 3468

East Asian (EAS) AF: 0.636 AC: 3283 AN: 5160

South Asian (SAS) AF: 0.601 AC: 2890 AN: 4808

European-Finnish (FIN) AF: 0.445 AC: 4700 AN: 10552

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.496 AC: 33699 AN: 67976

Other (OTH) AF: 0.472 AC: 996 AN: 2108

Alfa AF: 0.477 Hom.: 56979

Bravo AF: 0.421

Asia WGS AF: 0.589 AC: 2047 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.030
DANN	Benign	0.57
PhyloP100		-2.3
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: rs551491; hg19: chr10-131397821;