12-103986956-G-A

Variant names:

• chr12-103986956-G-A
• rs2888805
• NM_003211.6:c.1099G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003211.6(TDG):​c.1099G>A​(p.Val367Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0995 in 1,610,026 control chromosomes in the GnomAD database, including 4,775 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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 the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V367L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.082 (635 hom., cov: 41)
  • Exomes 𝑓: 0.10 (4140 hom.)
• Consequence: TDG NM_003211.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0730

Genes affected

TDG (HGNC:11700): (thymine DNA glycosylase) The protein encoded by this gene belongs to the TDG/mug DNA glycosylase family. Thymine-DNA glycosylase (TDG) removes thymine moieties from G/T mismatches by hydrolyzing the carbon-nitrogen bond between the sugar-phosphate backbone of DNA and the mispaired thymine. With lower activity, this enzyme also removes thymine from C/T and T/T mispairings. TDG can also remove uracil and 5-bromouracil from mispairings with guanine. This enzyme plays a central role in cellular defense against genetic mutation caused by the spontaneous deamination of 5-methylcytosine and cytosine. This gene may have a pseudogene in the p arm of chromosome 12. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046926737).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDG	NM_003211.6	c.1099G>A	p.Val367Met	missense_variant	Exon 10 of 10	ENST00000392872.8	NP_003202.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDG	ENST00000392872.8	c.1099G>A	p.Val367Met	missense_variant	Exon 10 of 10	1	NM_003211.6	ENSP00000376611.3

Frequencies

GnomAD3 genomes AF: 0.0822 AC: 12496 AN: 151964 Hom.: 636 Cov.: 41

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.0972

Gnomad ASJ AF: 0.0643

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.0896

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0988

Gnomad OTH AF: 0.0798

GnomAD2 exomes AF: 0.109 AC: 27239 AN: 250768 AF XY: 0.106

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.0620

Gnomad EAS exome AF: 0.281

Gnomad FIN exome AF: 0.0957

Gnomad NFE exome AF: 0.0990

Gnomad OTH exome AF: 0.0910

GnomAD4 exome AF: 0.101 AC: 147630 AN: 1457946 Hom.: 4140 Cov.: 33 AF XY: 0.101 AC XY: 73199 AN XY: 725322

Gnomad4 AFR exome AF: 0.0143 AC: 478 AN: 33464

Gnomad4 AMR exome AF: 0.130 AC: 5788 AN: 44528

Gnomad4 ASJ exome AF: 0.0617 AC: 1609 AN: 26092

Gnomad4 EAS exome AF: 0.283 AC: 11023 AN: 38946

Gnomad4 SAS exome AF: 0.0876 AC: 7538 AN: 86074

Gnomad4 FIN exome AF: 0.101 AC: 5352 AN: 53200

Gnomad4 NFE exome AF: 0.0988 AC: 109654 AN: 1109646

Gnomad4 Remaining exome AF: 0.0976 AC: 5878 AN: 60234

GnomAD4 genome AF: 0.0822 AC: 12498 AN: 152080 Hom.: 635 Cov.: 41 AF XY: 0.0845 AC XY: 6279 AN XY: 74336

Gnomad4 AFR AF: 0.0197 AC: 0.0197451 AN: 0.0197451

Gnomad4 AMR AF: 0.0973 AC: 0.097315 AN: 0.097315

Gnomad4 ASJ AF: 0.0643 AC: 0.0643022 AN: 0.0643022

Gnomad4 EAS AF: 0.289 AC: 0.288522 AN: 0.288522

Gnomad4 SAS AF: 0.0896 AC: 0.0896423 AN: 0.0896423

Gnomad4 FIN AF: 0.100 AC: 0.100019 AN: 0.100019

Gnomad4 NFE AF: 0.0988 AC: 0.0988109 AN: 0.0988109

Gnomad4 OTH AF: 0.0795 AC: 0.0794702 AN: 0.0794702

Alfa AF: 0.0951 Hom.: 1373

ESP6500AA AF: 0.0220 AC: 97

ESP6500EA AF: 0.0972 AC: 836

ExAC AF: 0.109 AC: 13237

Asia WGS AF: 0.159 AC: 551 AN: 3478

EpiCase AF: 0.0944

EpiControl AF: 0.0839

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.3
DANN	Benign	0.84
DEOGEN2	Benign	0.056	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.56	T;T;T
MetaRNN	Benign	0.0047	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.59	N;N;N
REVEL	Benign	0.056
Sift	Benign	0.085	T;T;T
Sift4G	Benign	0.085	T;T;T
Polyphen		0.074	B;.;.
Vest4		0.030
MPC		0.54
ClinPred		0.0017	T
GERP RS		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.019
gMVP		0.30
Mutation Taster		=92/8	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

Publications

LitVar

Other links and lift over

dbSNP: rs2888805; hg19: chr12-104380734; COSMIC: COSV57165549; COSMIC: COSV57165549;