4-105275613-G-A

Position:

chr4-105275613-G-A

Variant summary

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

The NM_001127208.3(TET2):c.5103G>A(p.Met1701Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00508 in 1,551,802 control chromosomes in the GnomAD database, including 26 homozygotes. 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 Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0038 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 22 hom. )

Consequence

TET2
NM_001127208.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 1.54

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=0.0052095056).

BP6

Variant 4-105275613-G-A is Benign according to our data. Variant chr4-105275613-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 135296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-105275613-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00379 (577/152252) while in subpopulation NFE AF= 0.00601 (409/68010). AF 95% confidence interval is 0.00553. There are 4 homozygotes in gnomad4. There are 273 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TET2	NM_001127208.3 linkuse as main transcript	c.5103G>A	p.Met1701Ile	missense_variant	11/11	ENST00000380013.9	NP_001120680.1
TET2-AS1	NR_126420.1 linkuse as main transcript	n.318+58773C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TET2	ENST00000380013.9 linkuse as main transcript	c.5103G>A	p.Met1701Ile	missense_variant	11/11	5	NM_001127208.3	ENSP00000369351	A2	Q6N021-1
TET2	ENST00000513237.5 linkuse as main transcript	c.5166G>A	p.Met1722Ile	missense_variant	11/11	1		ENSP00000425443	P4
TET2	ENST00000540549.5 linkuse as main transcript	c.5103G>A	p.Met1701Ile	missense_variant	11/11	1		ENSP00000442788	A2	Q6N021-1
TET2	ENST00000265149.9 linkuse as main transcript	c.*1427G>A		3_prime_UTR_variant, NMD_transcript_variant	10/10	5		ENSP00000265149		Q6N021-3

Frequencies

GnomAD3 genomes

AF:

0.00380

AC:

578

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00782

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00601

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00419

AC:

659

AN:

157378

Hom.:

AF XY:

0.00404

AC XY:

336

AN XY:

83136

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.000352

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000615

Gnomad FIN exome

AF:

0.0118

Gnomad NFE exome

AF:

0.00647

Gnomad OTH exome

AF:

0.00270

GnomAD4 exome

AF:

0.00522

AC:

7307

AN:

1399550

Hom.:

Cov.:

AF XY:

0.00516

AC XY:

3564

AN XY:

690284

show subpopulations

Gnomad4 AFR exome

AF:

0.000791

Gnomad4 AMR exome

AF:

0.00185

Gnomad4 ASJ exome

AF:

0.000437

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000757

Gnomad4 FIN exome

AF:

0.00977

Gnomad4 NFE exome

AF:

0.00598

Gnomad4 OTH exome

AF:

0.00358

GnomAD4 genome

AF:

0.00379

AC:

577

AN:

152252

Hom.:

Cov.:

AF XY:

0.00367

AC XY:

273

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00782

Gnomad4 NFE

AF:

0.00601

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00580

Hom.:

Bravo

AF:

0.00342

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.00786

AC:

ExAC

AF:

0.00344

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TET2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 24, 2021	- -

TET2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 24, 2020

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0081

T;T;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.61

T;T;.

MetaRNN

Benign

0.0052

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.2

.;M;M

MutationTaster

Benign

0.99

D;D;D;D

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.56

N;N;N

REVEL

Benign

0.052

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.38

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.18

MutPred

0.20

Loss of disorder (P = 0.0831);.;.;

MVP

0.26

MPC

0.078

ClinPred

0.011

GERP RS

1.6

Varity_R

0.040

gMVP

0.31

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