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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 28 publications found

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003211.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDG	NM_003211.6	MANE Select	c.1099G>A	p.Val367Met	missense	Exon 10 of 10	NP_003202.3
	TDG	NM_001363612.2		c.670G>A	p.Val224Met	missense	Exon 9 of 9	NP_001350541.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDG	ENST00000392872.8	TSL:1 MANE Select	c.1099G>A	p.Val367Met	missense	Exon 10 of 10	ENSP00000376611.3
	TDG	ENST00000266775.13	TSL:1	c.1087G>A	p.Val363Met	missense	Exon 11 of 11	ENSP00000266775.9
	TDG	ENST00000544861.5	TSL:2	c.670G>A	p.Val224Met	missense	Exon 9 of 9	ENSP00000445899.1

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

African (AFR) AF: 0.0143 AC: 478 AN: 33464

American (AMR) AF: 0.130 AC: 5788 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.0617 AC: 1609 AN: 26092

East Asian (EAS) AF: 0.283 AC: 11023 AN: 38946

South Asian (SAS) AF: 0.0876 AC: 7538 AN: 86074

European-Finnish (FIN) AF: 0.101 AC: 5352 AN: 53200

Middle Eastern (MID) AF: 0.0538 AC: 310 AN: 5762

European-Non Finnish (NFE) AF: 0.0988 AC: 109654 AN: 1109646

Other (OTH) 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

African (AFR) AF: 0.0197 AC: 821 AN: 41580

American (AMR) AF: 0.0973 AC: 1486 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0643 AC: 223 AN: 3468

East Asian (EAS) AF: 0.289 AC: 1468 AN: 5088

South Asian (SAS) AF: 0.0896 AC: 431 AN: 4808

European-Finnish (FIN) AF: 0.100 AC: 1060 AN: 10598

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0988 AC: 6714 AN: 67948

Other (OTH) AF: 0.0795 AC: 168 AN: 2114

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 v4.9

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
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.073
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.056
Sift	Benign	0.085	T
Sift4G	Benign	0.085	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

Other links and lift over

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