chr10-129613356-T-C

Variant names:

• chr10-129613356-T-C
• rs569235
• NM_002412.5:c.125+76979T>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+76979T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 152,118 control chromosomes in the GnomAD database, including 14,503 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 0.42 (14503 hom., cov: 33)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.337
• Publications: 4 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.125+76979T>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+76979T>C		intron_variant	Intron 2 of 4		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.218+76979T>C		intron_variant	Intron 2 of 4	1		ENSP00000302111.7

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64321 AN: 152000 Hom.: 14500 Cov.: 33

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.641

Gnomad SAS AF: 0.553

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.451

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

GnomAD4 genome AF: 0.423 AC: 64336 AN: 152118 Hom.: 14503 Cov.: 33 AF XY: 0.424 AC XY: 31505 AN XY: 74346

African (AFR) AF: 0.262 AC: 10875 AN: 41490

American (AMR) AF: 0.446 AC: 6822 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1717 AN: 3464

East Asian (EAS) AF: 0.641 AC: 3314 AN: 5172

South Asian (SAS) AF: 0.553 AC: 2669 AN: 4824

European-Finnish (FIN) AF: 0.440 AC: 4668 AN: 10600

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.482 AC: 32772 AN: 67972

Other (OTH) AF: 0.453 AC: 959 AN: 2116

Alfa AF: 0.431 Hom.: 1926

Bravo AF: 0.416

Asia WGS AF: 0.555 AC: 1931 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	0.34
DANN	Benign	0.37
PhyloP100		-0.34
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: rs569235; hg19: chr10-131411620;