Variant 2-73986482-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001287491.2(TET3):c.79G>A(p.Val27Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000416 in 1,232,166 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 7/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 1 hom. )

Consequence

TET3
NM_001287491.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.91

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.01657772).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000479 (73/152292) while in subpopulation AMR AF= 0.00085 (13/15300). AF 95% confidence interval is 0.000651. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TET3	NM_001287491.2 link	c.79G>A	p.Val27Ile	missense_variant	2/12	ENST00000409262.8	NP_001274420.1	O43151-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TET3	ENST00000409262.8 link	c.79G>A	p.Val27Ile	missense_variant	2/12	1	NM_001287491.2	ENSP00000386869.3		O43151-1
TET3	ENST00000496886.1 link	n.-44G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000823

Gnomad OTH

AF:

0.000479

GnomAD4 exome

AF:

0.000407

AC:

439

AN:

1079874

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

226

AN XY:

509802

show subpopulations

Gnomad4 AFR exome

AF:

0.0000871

Gnomad4 AMR exome

AF:

0.000356

Gnomad4 ASJ exome

AF:

0.000139

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000103

Gnomad4 FIN exome

AF:

0.0000466

Gnomad4 NFE exome

AF:

0.000437

Gnomad4 OTH exome

AF:

0.000550

GnomAD4 genome

AF:

0.000479

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000823

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000688

Hom.:

Bravo

AF:

0.000363

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1191281). This variant has not been reported in the literature in individuals affected with TET3-related conditions. This variant is present in population databases (rs142623499, gnomAD 0.4%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 27 of the TET3 protein (p.Val27Ile). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2023	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis does not support a benign or deleterious effect of this variant on protein structure/function -

Beck-Fahrner syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

May 05, 2023

This sequence variant is a single nucleotide substitution (G>A) at coding position 79 of the TET3 gene that results in a valine to isoleucine amino acid change at residue 27 of the TET3 protein. This is a previously reported variant (ClinVar) that has not been observed in the literature in individuals with TET3-related disorders, to our knowledge. This variant is present in the gnomAD population database (19 of 31392 alleles or 0.06%). Multiple bioinformatic tools predict that this variant would be tolerated; however, the Val27 residue is well conserved across the vertebrate species examined. Functiol studies testing the effect of this variant on protein structure or activity have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this to be a variant of uncertain significance. ACMG Criteria: -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.82

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.68

MetaRNN

Benign

0.017

Sift4G

Benign

0.59

Vest4

0.20

MVP

0.15

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.093

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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