10-129716127-T-C

Variant names:

• chr10-129716127-T-C
• rs4750768
• NM_002412.5:c.274+8084T>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.274+8084T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 152,014 control chromosomes in the GnomAD database, including 11,076 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 0.37 (11076 hom., cov: 33)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.56
• 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]

LOC105378560 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.274+8084T>C		intron_variant	Intron 3 of 4	ENST00000651593.1	NP_002403.3
LOC105378560	XR_946467.3	n.7555+523T>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.274+8084T>C		intron_variant	Intron 3 of 4		NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.367+8084T>C		intron_variant	Intron 3 of 4	1		ENSP00000302111.7
MGMT	ENST00000462672.1	n.520+523T>C		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56791 AN: 151896 Hom.: 11059 Cov.: 33

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.688

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.380

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

GnomAD4 genome AF: 0.374 AC: 56842 AN: 152014 Hom.: 11076 Cov.: 33 AF XY: 0.378 AC XY: 28053 AN XY: 74290

African (AFR) AF: 0.408 AC: 16909 AN: 41466

American (AMR) AF: 0.365 AC: 5579 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1083 AN: 3472

East Asian (EAS) AF: 0.688 AC: 3553 AN: 5166

South Asian (SAS) AF: 0.487 AC: 2342 AN: 4808

European-Finnish (FIN) AF: 0.362 AC: 3820 AN: 10550

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.330 AC: 22414 AN: 67958

Other (OTH) AF: 0.386 AC: 817 AN: 2114

Alfa AF: 0.347 Hom.: 11543

Bravo AF: 0.376

Asia WGS AF: 0.594 AC: 2061 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.027
DANN	Benign	0.35
PhyloP100		-2.6
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: rs4750768; hg19: chr10-131514391;