10-129716598-A-G

Position:

• chr10-129716598-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002412.5(MGMT):​c.274+8555A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 152,056 control chromosomes in the GnomAD database, including 30,824 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 0.63 (30824 hom., cov: 33)
• Consequence: MGMT NM_002412.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.725

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]

MGMT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGMT	NM_002412.5	c.274+8555A>G		intron_variant		ENST00000651593.1	NP_002403.3
LOC105378560	XR_946467.3	n.7555+994A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.274+8555A>G		intron_variant			NM_002412.5	ENSP00000498729.1
MGMT	ENST00000306010.8	c.367+8555A>G		intron_variant		1		ENSP00000302111.7
MGMT	ENST00000462672.1	n.520+994A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.626 AC: 95135 AN: 151938 Hom.: 30807 Cov.: 33

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.637

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.662

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.732

Gnomad OTH AF: 0.637

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

GnomAD4 genome AF: 0.626 AC: 95182 AN: 152056 Hom.: 30824 Cov.: 33 AF XY: 0.617 AC XY: 45902 AN XY: 74336

Gnomad4 AFR AF: 0.481

Gnomad4 AMR AF: 0.546

Gnomad4 ASJ AF: 0.637

Gnomad4 EAS AF: 0.646

Gnomad4 SAS AF: 0.663

Gnomad4 FIN AF: 0.591

Gnomad4 NFE AF: 0.732

Gnomad4 OTH AF: 0.640

Alfa AF: 0.708 Hom.: 39043

Bravo AF: 0.613

Asia WGS AF: 0.669 AC: 2326 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	0.024
DANN	Benign	0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs10764901; hg19: chr10-131514862;