rs2888805

Positions:

• chr12-103986956-G-A
• chr12-103986956-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000392872.8(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. 14/20 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 same amino acid change has been previously reported as Likely benignin 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 ENST00000392872.8 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

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
TDG	NM_003211.6	c.1099G>A	p.Val367Met	missense_variant	10/10	ENST00000392872.8	NP_003202.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TDG	ENST00000392872.8	c.1099G>A	p.Val367Met	missense_variant	10/10	1	NM_003211.6	ENSP00000376611	P1

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

GnomAD3 exomes AF: 0.109 AC: 27239 AN: 250768 Hom.: 1227 AF XY: 0.106 AC XY: 14303 AN XY: 135530

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 SAS exome AF: 0.0865

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

Gnomad4 AMR exome AF: 0.130

Gnomad4 ASJ exome AF: 0.0617

Gnomad4 EAS exome AF: 0.283

Gnomad4 SAS exome AF: 0.0876

Gnomad4 FIN exome AF: 0.101

Gnomad4 NFE exome AF: 0.0988

Gnomad4 OTH exome AF: 0.0976

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

Gnomad4 AMR AF: 0.0973

Gnomad4 ASJ AF: 0.0643

Gnomad4 EAS AF: 0.289

Gnomad4 SAS AF: 0.0896

Gnomad4 FIN AF: 0.100

Gnomad4 NFE AF: 0.0988

Gnomad4 OTH AF: 0.0795

Alfa AF: 0.0974 Hom.: 847

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;.;.
MutationTaster	Benign	1.0	P;P;P;P
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

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;