2-73986473-C-T

Position:

• chr2-73986473-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001287491.2(TET3):​c.70C>T​(p.Gln24*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TET3 NM_001287491.2 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.47

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-73986473-C-T is Pathogenic according to our data. Variant chr2-73986473-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3376267.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TET3	NM_001287491.2	c.70C>T	p.Gln24*	stop_gained	2/12	ENST00000409262.8	NP_001274420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TET3	ENST00000409262.8	c.70C>T	p.Gln24*	stop_gained	2/12	1	NM_001287491.2	ENSP00000386869.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Beck-Fahrner syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Aug 22, 2023

This sequence variant is a single nucleotide substitution (C>T) at coding position 70 of the TET3 gene that generates a premature stop codon at residue 24 of the TET3 protein. This variant is predicted to generate a non-functiol allele through either the expression of a truncated protein or a loss of TET3 expression due to nonsense mediated decay. This is a novel variant that has not been previously reported in databases of clinically annotated variants (ClinVar) or observed in the literature in individuals with TET3-related disease. This variant is absent from control population datasets (gnomAD database 0 of ~31,000 alleles). Because loss of function alleles in TET3 are known to be pathogenic (PMID 31928709), we consider this variant to be likely pathogenic. ACMG Criteria: PM2, PVS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	36
DANN	Benign	0.84
FATHMM_MKL	Benign	0.55	D
Vest4		0.50
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-74213600;