chr10-129766794-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002412.5(MGMT):​c.421A>G​(p.Ile141Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Consequence

MGMT
NM_002412.5 missense

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.94
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.25923455).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MGMTNM_002412.5 linkuse as main transcriptc.421A>G p.Ile141Val missense_variant 5/5 ENST00000651593.1 NP_002403.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MGMTENST00000651593.1 linkuse as main transcriptc.421A>G p.Ile141Val missense_variant 5/5 NM_002412.5 ENSP00000498729 P1
MGMTENST00000306010.8 linkuse as main transcriptc.514A>G p.Ile172Val missense_variant 5/51 ENSP00000302111

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 26, 2023The c.514A>G (p.I172V) alteration is located in exon 5 (coding exon 5) of the MGMT gene. This alteration results from a A to G substitution at nucleotide position 514, causing the isoleucine (I) at amino acid position 172 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
19
DANN
Uncertain
1.0
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.070
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.86
D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.26
T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
0.99
D
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.92
N
REVEL
Benign
0.042
Sift
Benign
0.045
D
Sift4G
Benign
0.14
T
Vest4
0.20
MutPred
0.70
Gain of sheet (P = 0.1208);
MVP
0.22
MPC
0.062
ClinPred
0.68
D
GERP RS
3.8
gMVP
0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-131565058; API