rs4135128

Positions:

• chr12-103985545-G-C

Variant summary

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

The NM_003211.6(TDG):​c.965-58G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0913 in 1,534,176 control chromosomes in the GnomAD database, including 7,489 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.080 (691 hom., cov: 32)
  • Exomes 𝑓: 0.093 (6798 hom.)
• Consequence: TDG NM_003211.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.134

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]

TDG (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TDG	NM_003211.6	c.965-58G>C		intron_variant		ENST00000392872.8	NP_003202.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TDG	ENST00000392872.8	c.965-58G>C		intron_variant		1	NM_003211.6	ENSP00000376611.3

Frequencies

GnomAD3 genomes AF: 0.0803 AC: 12223 AN: 152126 Hom.: 691 Cov.: 32

Gnomad AFR AF: 0.0291

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0533

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0904

Gnomad OTH AF: 0.0784

GnomAD4 exome AF: 0.0925 AC: 127877 AN: 1381932 Hom.: 6798 AF XY: 0.0951 AC XY: 65063 AN XY: 684124

Gnomad4 AFR exome AF: 0.0291

Gnomad4 AMR exome AF: 0.0379

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.154

Gnomad4 FIN exome AF: 0.126

Gnomad4 NFE exome AF: 0.0855

Gnomad4 OTH exome AF: 0.0961

GnomAD4 genome AF: 0.0803 AC: 12229 AN: 152244 Hom.: 691 Cov.: 32 AF XY: 0.0844 AC XY: 6284 AN XY: 74424

Gnomad4 AFR AF: 0.0291

Gnomad4 AMR AF: 0.0531

Gnomad4 ASJ AF: 0.118

Gnomad4 EAS AF: 0.216

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.0904

Gnomad4 OTH AF: 0.0771

Alfa AF: 0.0833 Hom.: 70

Bravo AF: 0.0721

Asia WGS AF: 0.170 AC: 592 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.56

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: rs4135128; hg19: chr12-104379323; COSMIC: COSV57165574; COSMIC: COSV57165574;