ENST00000306010.8:c.34G>T

Variant names:

• chr10-129467249-G-T
• rs1440359481
• ENST00000306010.8:c.34G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000306010.8(MGMT):​c.34G>T​(p.Ala12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000816 in 1,470,042 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: MGMT ENST00000306010.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.245
• Publications: 3 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]

ENSG00000296036 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07321501).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5	c.-60G>T		5_prime_UTR_variant	Exon 1 of 5	ENST00000651593.1	NP_002403.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGMT	ENST00000651593.1	c.-60G>T		5_prime_UTR_variant	Exon 1 of 5		NM_002412.5	ENSP00000498729.1

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 151034 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000587

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000552 AC: 8 AN: 145044 AF XY: 0.0000128

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000826

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000682 AC: 9 AN: 1318890 Hom.: 0 Cov.: 39 AF XY: 0.00000307 AC XY: 2 AN XY: 650742

African (AFR) AF: 0.00 AC: 0 AN: 28544

American (AMR) AF: 0.00 AC: 0 AN: 32568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22162

East Asian (EAS) AF: 0.000206 AC: 6 AN: 29116

South Asian (SAS) AF: 0.00 AC: 0 AN: 77956

European-Finnish (FIN) AF: 0.0000267 AC: 1 AN: 37520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5296

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1032954

Other (OTH) AF: 0.0000379 AC: 2 AN: 52774

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151152 Hom.: 0 Cov.: 34 AF XY: 0.0000406 AC XY: 3 AN XY: 73870

African (AFR) AF: 0.00 AC: 0 AN: 41286

American (AMR) AF: 0.00 AC: 0 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.000588 AC: 3 AN: 5102

South Asian (SAS) AF: 0.00 AC: 0 AN: 4760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67780

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34G>T (p.A12S) alteration is located in exon 1 (coding exon 1) of the MGMT gene. This alteration results from a G to T substitution at nucleotide position 34, causing the alanine (A) at amino acid position 12 to be replaced by a serine (S). 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
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.9
DANN	Uncertain	0.99
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.96	T
PhyloP100		0.24
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.079
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.19
MutPred		0.26		Gain of loop (P = 0.0166);
MVP		0.33
MPC		0.11
ClinPred		0.59	D
GERP RS		3.3
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.31
Mutation Taster		=86/14	polymorphism

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: rs1440359481; hg19: chr10-131265513;