rs142312318

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001127208.3(TET2):c.5152G>T(p.Val1718Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00651 in 1,551,956 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0043 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0068 ( 31 hom. )

Consequence

TET2
NM_001127208.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: -0.0290

Variant links:

Genes affected

TET2 (HGNC:25941): (tet methylcytosine dioxygenase 2) The protein encoded by this gene is a methylcytosine dioxygenase that catalyzes the conversion of methylcytosine to 5-hydroxymethylcytosine. The encoded protein is involved in myelopoiesis, and defects in this gene have been associated with several myeloproliferative disorders. Two variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]

TET2 links:

TET2-AS1 (HGNC:):

TET2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058729947).

BP6

Variant 4-105275662-G-T is Benign according to our data. Variant chr4-105275662-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 135297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00427 (650/152322) while in subpopulation NFE AF= 0.00705 (480/68038). AF 95% confidence interval is 0.00653. There are 4 homozygotes in gnomad4. There are 276 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TET2	NM_001127208.3 linkuse as main transcript	c.5152G>T	p.Val1718Leu	missense_variant	11/11	ENST00000380013.9
TET2-AS1	NR_126420.1 linkuse as main transcript	n.318+58724C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TET2	ENST00000380013.9 linkuse as main transcript	c.5152G>T	p.Val1718Leu	missense_variant	11/11	5	NM_001127208.3	A2	Q6N021-1
TET2	ENST00000513237.5 linkuse as main transcript	c.5215G>T	p.Val1739Leu	missense_variant	11/11	1		P4
TET2	ENST00000540549.5 linkuse as main transcript	c.5152G>T	p.Val1718Leu	missense_variant	11/11	1		A2	Q6N021-1
TET2	ENST00000265149.9 linkuse as main transcript	c.*1476G>T		3_prime_UTR_variant, NMD_transcript_variant	10/10	5			Q6N021-3

Frequencies

GnomAD3 genomes

AF:

0.00427

AC:

650

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00536

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00705

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00361

AC:

569

AN:

157498

Hom.:

AF XY:

0.00365

AC XY:

303

AN XY:

83116

show subpopulations

Gnomad AFR exome

AF:

0.000977

Gnomad AMR exome

AF:

0.00117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.00497

Gnomad NFE exome

AF:

0.00668

Gnomad OTH exome

AF:

0.00247

GnomAD4 exome

AF:

0.00675

AC:

9450

AN:

1399634

Hom.:

Cov.:

AF XY:

0.00652

AC XY:

4502

AN XY:

690306

show subpopulations

Gnomad4 AFR exome

AF:

0.00101

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.000159

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00126

Gnomad4 FIN exome

AF:

0.00557

Gnomad4 NFE exome

AF:

0.00806

Gnomad4 OTH exome

AF:

0.00511

GnomAD4 genome

AF:

0.00427

AC:

650

AN:

152322

Hom.:

Cov.:

AF XY:

0.00371

AC XY:

276

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00161

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00536

Gnomad4 NFE

AF:

0.00705

Gnomad4 OTH

AF:

0.00425

Alfa

AF:

0.00631

Hom.:

Bravo

AF:

0.00399

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.00660

AC:

ExAC

AF:

0.00266

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TET2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	- -

TET2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.72

Cadd

Benign

0.25

Dann

Benign

0.41

DEOGEN2

Benign

0.010

T;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.61

T;T;.

M_CAP

Benign

0.021

MetaRNN

Benign

0.0059

T;T;T

MetaSVM

Benign

-0.90

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.34

N;N;N

REVEL

Benign

0.0050

Sift

Benign

0.38

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0070

B;B;B

Vest4

0.044

MutPred

0.25

Gain of catalytic residue at V1739 (P = 0.0405);.;.;

MVP

0.22

MPC

0.070

ClinPred

0.00035

GERP RS

-2.3

Varity_R

0.018

gMVP

0.30

Splicing

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