rs17035056

Positions:

• chr12-103973037-G-A

Variant summary

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

The ENST00000266775.13(TDG):​c.11+4G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0232 in 701,106 control chromosomes in the GnomAD database, including 1,656 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 0.016 (246 hom., cov: 32)
  • Exomes 𝑓: 0.025 (1410 hom.)
• Consequence: TDG ENST00000266775.13 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00003497
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.432

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 (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TDG	NM_003211.6	c.24-3881G>A		intron_variant		ENST00000392872.8
TDG	NM_001363612.2	c.-263-6794G>A		intron_variant
TDG	XM_047429486.1	c.11+4G>A		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDG	ENST00000392872.8	c.24-3881G>A		intron_variant		1	NM_003211.6	P1

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2479 AN: 151232 Hom.: 246 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.0322

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000486

Gnomad OTH AF: 0.0192

GnomAD3 exomes AF: 0.0412 AC: 5519 AN: 134090 Hom.: 535 AF XY: 0.0377 AC XY: 2753 AN XY: 73068

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.0762

Gnomad ASJ exome AF: 0.000362

Gnomad EAS exome AF: 0.290

Gnomad SAS exome AF: 0.0222

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000417

Gnomad OTH exome AF: 0.0249

GnomAD4 exome AF: 0.0251 AC: 13798 AN: 549792 Hom.: 1410 Cov.: 0 AF XY: 0.0241 AC XY: 7177 AN XY: 297662

Gnomad4 AFR exome AF: 0.00285

Gnomad4 AMR exome AF: 0.0729

Gnomad4 ASJ exome AF: 0.000350

Gnomad4 EAS exome AF: 0.273

Gnomad4 SAS exome AF: 0.0237

Gnomad4 FIN exome AF: 0.0000597

Gnomad4 NFE exome AF: 0.000708

Gnomad4 OTH exome AF: 0.0244

GnomAD4 genome AF: 0.0164 AC: 2485 AN: 151314 Hom.: 246 Cov.: 32 AF XY: 0.0189 AC XY: 1394 AN XY: 73812

Gnomad4 AFR AF: 0.00286

Gnomad4 AMR AF: 0.0437

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.287

Gnomad4 SAS AF: 0.0323

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000486

Gnomad4 OTH AF: 0.0196

Alfa AF: 0.0106 Hom.: 19

Bravo AF: 0.0211

Asia WGS AF: 0.135 AC: 467 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	8.8
DANN	Benign	0.28

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000035
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		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: rs17035056; hg19: chr12-104366815;