rs200971953

Positions:

chr4-105276395-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_001127208.3(TET2):c.5885C>T(p.Pro1962Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000523 in 1,551,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00054 ( 0 hom. )

Consequence

TET2
NM_001127208.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3O:1

Conservation

PhyloP100: 4.57

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 Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2392289).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000362 (55/152080) while in subpopulation NFE AF= 0.000632 (43/68006). AF 95% confidence interval is 0.000482. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 31. 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
TET2	NM_001127208.3 linkuse as main transcript	c.5885C>T	p.Pro1962Leu	missense_variant	11/11	ENST00000380013.9	NP_001120680.1	Q6N021-1A0A158SIU0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TET2	ENST00000380013.9 linkuse as main transcript	c.5885C>T	p.Pro1962Leu	missense_variant	11/11	5	NM_001127208.3	ENSP00000369351.4		Q6N021-1

Frequencies

GnomAD3 genomes

AF:

0.000362

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000632

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000215

AC:

AN:

157912

Hom.:

AF XY:

0.000252

AC XY:

AN XY:

83358

show subpopulations

Gnomad AFR exome

AF:

0.000122

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000591

Gnomad NFE exome

AF:

0.000521

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000541

AC:

757

AN:

1399710

Hom.:

Cov.:

AF XY:

0.000532

AC XY:

367

AN XY:

690338

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000121

Gnomad4 NFE exome

AF:

0.000669

Gnomad4 OTH exome

AF:

0.000465

GnomAD4 genome

AF:

0.000362

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.000431

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.000242

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000314

Hom.:

Bravo

AF:

0.000325

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000314

AC:

ExAC

AF:

0.0000391

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 16, 2024	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 24, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1962 of the TET2 protein (p.Pro1962Leu). This variant is present in population databases (rs200971953, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of acute myeloid leukemia or myelodysplastic syndrome (PMID: 22390313, 32098966). ClinVar contains an entry for this variant (Variation ID: 135294). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	TET2: PM2:Supporting, BP4 -

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

0.27

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

D;D;.

M_CAP

Benign

0.036

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

.;M;M

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-4.9

D;D;D

REVEL

Benign

0.20

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.016

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.29

MVP

0.60

MPC

0.36

ClinPred

0.63

GERP RS

4.7

Varity_R

0.22

gMVP

0.44

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