Variant chr2-74046381-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001287491.2(TET3):c.464C>T(p.Pro155Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 1,540,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

TET3
NM_001287491.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.839

Variant links:

Genes affected

TET3 (HGNC:28313): (tet methylcytosine dioxygenase 3) Enables methyl-CpG binding activity and zinc ion binding activity. Involved in histone H3-K4 trimethylation; positive regulation of transcription by RNA polymerase II; and protein O-linked glycosylation. Predicted to be located in cytoplasm and male pronucleus. Predicted to be active in nucleus. Biomarker of esophagus squamous cell carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

TET3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TET3. . Gene score misZ 2.878 (greater than the threshold 3.09). Trascript score misZ 3.5386 (greater than threshold 3.09). GenCC has associacion of gene with Beck-Fahrner syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.10474384).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TET3	NM_001287491.2 linkuse as main transcript	c.464C>T	p.Pro155Leu	missense_variant	4/12	ENST00000409262.8	NP_001274420.1	O43151-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TET3	ENST00000409262.8 linkuse as main transcript	c.464C>T	p.Pro155Leu	missense_variant	4/12	1	NM_001287491.2	ENSP00000386869.3		O43151-1
TET3	ENST00000305799.8 linkuse as main transcript	c.185C>T	p.Pro62Leu	missense_variant	3/11	5		ENSP00000307803.8		A0A5H1ZRP3

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000270

AC:

AN:

185314

Hom.:

AF XY:

0.0000102

AC XY:

AN XY:

98330

show subpopulations

Gnomad AFR exome

AF:

0.000137

Gnomad AMR exome

AF:

0.0000839

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000113

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000108

AC:

AN:

1388622

Hom.:

Cov.:

AF XY:

0.00000877

AC XY:

AN XY:

683854

show subpopulations

Gnomad4 AFR exome

AF:

0.000129

Gnomad4 AMR exome

AF:

0.000122

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000463

Gnomad4 OTH exome

AF:

0.0000350

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.0000250

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2021

The c.59C>T (p.P20L) alteration is located in exon 1 (coding exon 1) of the TET3 gene. This alteration results from a C to T substitution at nucleotide position 59, causing the proline (P) at amino acid position 20 to be replaced by a leucine (L). 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

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.10

Eigen_PC

Benign

0.095

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.90

D;.

M_CAP

Benign

0.0077

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.3

.;N

REVEL

Benign

0.096

Sift

Uncertain

0.0040

.;D

Sift4G

Benign

0.28

T;D

Vest4

0.16

MVP

0.082

MPC

0.15

ClinPred

0.086

GERP RS

5.4

gMVP

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over