chr12-103982915-G-A

Variant names:

• chr12-103982915-G-A
• rs4135113
• NM_003211.6:c.595G>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.595G>A​(p.Gly199Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0333 in 1,613,864 control chromosomes in the GnomAD database, including 2,104 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 0.071 (725 hom., cov: 32)
  • Exomes 𝑓: 0.029 (1379 hom.)
• Consequence: TDG NM_003211.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.86
• Publications: 46 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=0.0018633008).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.163 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.595G>A	p.Gly199Ser	missense	Exon 5 of 10	NP_003202.3
	TDG	NM_001363612.2		c.166G>A	p.Gly56Ser	missense	Exon 4 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.595G>A	p.Gly199Ser	missense	Exon 5 of 10	ENSP00000376611.3
	TDG	ENST00000266775.13	TSL:1	c.583G>A	p.Gly195Ser	missense	Exon 6 of 11	ENSP00000266775.9
	TDG	ENST00000544861.5	TSL:2	c.166G>A	p.Gly56Ser	missense	Exon 4 of 9	ENSP00000445899.1

Frequencies

GnomAD3 genomes AF: 0.0713 AC: 10835 AN: 152022 Hom.: 721 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0703

Gnomad ASJ AF: 0.0680

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.0262

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0738

GnomAD2 exomes AF: 0.0467 AC: 11729 AN: 251310 AF XY: 0.0429

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.0573

Gnomad ASJ exome AF: 0.0651

Gnomad EAS exome AF: 0.144

Gnomad FIN exome AF: 0.0206

Gnomad NFE exome AF: 0.0208

Gnomad OTH exome AF: 0.0454

GnomAD4 exome AF: 0.0293 AC: 42814 AN: 1461724 Hom.: 1379 Cov.: 32 AF XY: 0.0291 AC XY: 21133 AN XY: 727176

African (AFR) AF: 0.169 AC: 5640 AN: 33424

American (AMR) AF: 0.0564 AC: 2520 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0613 AC: 1601 AN: 26128

East Asian (EAS) AF: 0.167 AC: 6624 AN: 39672

South Asian (SAS) AF: 0.0254 AC: 2187 AN: 86250

European-Finnish (FIN) AF: 0.0191 AC: 1020 AN: 53414

Middle Eastern (MID) AF: 0.0772 AC: 445 AN: 5762

European-Non Finnish (NFE) AF: 0.0182 AC: 20197 AN: 1111988

Other (OTH) AF: 0.0427 AC: 2580 AN: 60388

GnomAD4 genome AF: 0.0713 AC: 10847 AN: 152140 Hom.: 725 Cov.: 32 AF XY: 0.0715 AC XY: 5314 AN XY: 74364

African (AFR) AF: 0.166 AC: 6902 AN: 41464

American (AMR) AF: 0.0702 AC: 1072 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0680 AC: 236 AN: 3472

East Asian (EAS) AF: 0.150 AC: 776 AN: 5178

South Asian (SAS) AF: 0.0264 AC: 127 AN: 4812

European-Finnish (FIN) AF: 0.0191 AC: 202 AN: 10602

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0197 AC: 1340 AN: 68018

Other (OTH) AF: 0.0731 AC: 154 AN: 2108

Alfa AF: 0.0390 Hom.: 1031

Bravo AF: 0.0800

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.164 AC: 721

ESP6500EA AF: 0.0237 AC: 204

ExAC AF: 0.0467 AC: 5675

Asia WGS AF: 0.0810 AC: 284 AN: 3478

EpiCase AF: 0.0250

EpiControl AF: 0.0256

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.019
Eigen_PC	Benign	0.073
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		6.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.22
Sift	Benign	0.21	T
Sift4G	Benign	0.20	T
Polyphen		0.43	B
Vest4		0.20
MPC		0.63
ClinPred		0.067	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.86
Mutation Taster		=40/60	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: rs4135113; hg19: chr12-104376693; COSMIC: COSV57166750; COSMIC: COSV57166750;