12-103966044-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003211.6(TDG):c.7G>C(p.Ala3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,443,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

TDG
NM_003211.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.919

Publications

0 publications found

Variant links:

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 links:

ENSG00000288744 (HGNC:):

ENSG00000288744 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17476076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDG	NM_003211.6 link	c.7G>C	p.Ala3Pro	missense_variant	Exon 1 of 10	ENST00000392872.8	NP_003202.3	Q13569B4E127
TDG	NM_001363612.2 link	c.-280G>C		5_prime_UTR_variant	Exon 1 of 9		NP_001350541.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDG	ENST00000392872.8 link	c.7G>C	p.Ala3Pro	missense_variant	Exon 1 of 10	1	NM_003211.6	ENSP00000376611.3		Q13569

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000462

AC:

AN:

216538

AF XY:

0.00000840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000104

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000346

AC:

AN:

1443076

Hom.:

Cov.:

AF XY:

0.00000558

AC XY:

AN XY:

716906

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32444

American (AMR)

AF:

0.00

AC:

AN:

42686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25456

East Asian (EAS)

AF:

0.0000521

AC:

AN:

38424

South Asian (SAS)

AF:

0.0000238

AC:

AN:

84160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51026

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1103696

Other (OTH)

AF:

0.00

AC:

AN:

59490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.7G>C (p.A3P) alteration is located in exon 1 (coding exon 1) of the TDG gene. This alteration results from a G to C substitution at nucleotide position 7, causing the alanine (A) at amino acid position 3 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.034

T;T

Eigen

Benign

0.0038

Eigen_PC

Benign

-0.0053

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.67

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.4

L;.

PhyloP100

0.92

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.51

N;N

REVEL

Benign

0.082

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.032

D;D

Polyphen

0.70

P;.

Vest4

0.30

MutPred

0.25

Gain of catalytic residue at A3 (P = 0.0057);Gain of catalytic residue at A3 (P = 0.0057);

MVP

0.84

MPC

0.78

ClinPred

0.71

GERP RS

2.5

PromoterAI

0.017

Neutral

(source)

Varity_R

0.17

gMVP

0.61

Mutation Taster

=289/11

polymorphism

(source)

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

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12-103966044-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over