rs2308321

Positions:

• chr10-129766800-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.427A>G​(p.Ile143Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,612,120 control chromosomes in the GnomAD database, including 12,315 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.087 (829 hom., cov: 34)
  • Exomes 𝑓: 0.12 (11486 hom.)
• Consequence: MGMT NM_002412.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.66

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030550957).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGMT	NM_002412.5	c.427A>G	p.Ile143Val	missense_variant	5/5	ENST00000651593.1	NP_002403.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.427A>G	p.Ile143Val	missense_variant	5/5		NM_002412.5	ENSP00000498729	P1
MGMT	ENST00000306010.8	c.520A>G	p.Ile174Val	missense_variant	5/5	1		ENSP00000302111

Frequencies

GnomAD3 genomes AF: 0.0872 AC: 13276 AN: 152182 Hom.: 830 Cov.: 34

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.0719

Gnomad ASJ AF: 0.0761

Gnomad EAS AF: 0.0118

Gnomad SAS AF: 0.0750

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.0871

GnomAD3 exomes AF: 0.0927 AC: 22954 AN: 247730 Hom.: 1316 AF XY: 0.0970 AC XY: 13050 AN XY: 134516

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.0471

Gnomad ASJ exome AF: 0.0877

Gnomad EAS exome AF: 0.00885

Gnomad SAS exome AF: 0.0808

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.0986

GnomAD4 exome AF: 0.120 AC: 174673 AN: 1459820 Hom.: 11486 Cov.: 31 AF XY: 0.119 AC XY: 86520 AN XY: 726216

Gnomad4 AFR exome AF: 0.0180

Gnomad4 AMR exome AF: 0.0492

Gnomad4 ASJ exome AF: 0.0883

Gnomad4 EAS exome AF: 0.00496

Gnomad4 SAS exome AF: 0.0830

Gnomad4 FIN exome AF: 0.120

Gnomad4 NFE exome AF: 0.134

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.0871 AC: 13272 AN: 152300 Hom.: 829 Cov.: 34 AF XY: 0.0858 AC XY: 6393 AN XY: 74476

Gnomad4 AFR AF: 0.0224

Gnomad4 AMR AF: 0.0718

Gnomad4 ASJ AF: 0.0761

Gnomad4 EAS AF: 0.0116

Gnomad4 SAS AF: 0.0757

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.129

Gnomad4 OTH AF: 0.0871

Alfa AF: 0.118 Hom.: 2122

Bravo AF: 0.0799

TwinsUK AF: 0.143 AC: 531

ALSPAC AF: 0.129 AC: 497

ESP6500AA AF: 0.0225 AC: 99

ESP6500EA AF: 0.128 AC: 1104

ExAC AF: 0.0921 AC: 11173

Asia WGS AF: 0.0380 AC: 133 AN: 3478

EpiCase AF: 0.133

EpiControl AF: 0.127

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.7
DANN	Benign	0.55
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.86
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.051
Sift	Benign	0.51	T
Sift4G	Benign	0.47	T
Vest4		0.11
MPC		0.062
ClinPred		0.00077	T
GERP RS		-0.42
gMVP		0.43

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: rs2308321; hg19: chr10-131565064;