rs2308321

Variant names:

• chr10-129766800-A-G
• rs2308321
• NM_002412.5:c.427A>G

Variant summary

Our verdict is Benign. The variant received -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. 14/19 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. I143F) has been classified as Uncertain significance.

• 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
• Publications: 124 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 (MetaRNN=0.0030550957).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002412.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MGMT	NM_002412.5	MANE Select	c.427A>G	p.Ile143Val	missense	Exon 5 of 5	NP_002403.3	P16455

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MGMT	ENST00000651593.1	MANE Select	c.427A>G	p.Ile143Val	missense	Exon 5 of 5	ENSP00000498729.1	P16455
	MGMT	ENST00000306010.8	TSL:1	c.520A>G	p.Ile174Val	missense	Exon 5 of 5	ENSP00000302111.7	B4DEE8
	MGMT	ENST00000897068.1		c.427A>G	p.Ile143Val	missense	Exon 5 of 5	ENSP00000567127.1

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

GnomAD2 exomes AF: 0.0927 AC: 22954 AN: 247730 AF XY: 0.0970

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 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

African (AFR) AF: 0.0180 AC: 601 AN: 33456

American (AMR) AF: 0.0492 AC: 2197 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.0883 AC: 2303 AN: 26096

East Asian (EAS) AF: 0.00496 AC: 197 AN: 39694

South Asian (SAS) AF: 0.0830 AC: 7154 AN: 86142

European-Finnish (FIN) AF: 0.120 AC: 6339 AN: 52634

Middle Eastern (MID) AF: 0.0888 AC: 496 AN: 5588

European-Non Finnish (NFE) AF: 0.134 AC: 149006 AN: 1111262

Other (OTH) AF: 0.106 AC: 6380 AN: 60282

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

African (AFR) AF: 0.0224 AC: 931 AN: 41578

American (AMR) AF: 0.0718 AC: 1099 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0761 AC: 264 AN: 3470

East Asian (EAS) AF: 0.0116 AC: 60 AN: 5166

South Asian (SAS) AF: 0.0757 AC: 365 AN: 4824

European-Finnish (FIN) AF: 0.130 AC: 1380 AN: 10620

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8774 AN: 68012

Other (OTH) AF: 0.0871 AC: 184 AN: 2112

Alfa AF: 0.116 Hom.: 4288

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 v4.9

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
PhyloP100		1.7
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
Mutation Taster		=97/3	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: rs2308321; hg19: chr10-131565064; COSMIC: COSV107375270; COSMIC: COSV107375270;