Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001127208.3(TET2):c.1064G>A(p.Gly355Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0375 in 1,614,054 control chromosomes in the GnomAD database, including 1,339 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 89 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1250 hom. )

Consequence

TET2
NM_001127208.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.90

Publications

32 publications found

Variant links:

COSMIC-nc: COSV54398666

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:41125): (TET2 antisense RNA 1)

TET2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003620863).

BP6

Variant 4-105235006-G-A is Benign according to our data. Variant chr4-105235006-G-A is described in ClinVar as Benign. ClinVar VariationId is 135317.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 = 0.0281 (4272/152256) while in subpopulation NFE AF = 0.0428 (2914/68022). AF 95% confidence interval is 0.0415. There are 89 homozygotes in GnomAd4. There are 1958 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 89 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127208.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TET2	NM_001127208.3	MANE Select	c.1064G>A	p.Gly355Asp	missense	Exon 3 of 11	NP_001120680.1
TET2	NM_017628.4		c.1064G>A	p.Gly355Asp	missense	Exon 3 of 3	NP_060098.3
TET2-AS1	NR_126420.1		n.319-57334C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TET2	ENST00000380013.9	TSL:5 MANE Select	c.1064G>A	p.Gly355Asp	missense	Exon 3 of 11	ENSP00000369351.4
TET2	ENST00000513237.5	TSL:1	c.1127G>A	p.Gly376Asp	missense	Exon 3 of 11	ENSP00000425443.1
TET2	ENST00000540549.5	TSL:1	c.1064G>A	p.Gly355Asp	missense	Exon 3 of 11	ENSP00000442788.1

Frequencies

GnomAD3 genomes

AF:

0.0281

AC:

4275

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00811

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0341

Gnomad ASJ

AF:

0.0372

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.0193

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0428

Gnomad OTH

AF:

0.0368

GnomAD2 exomes

AF:

0.0288

AC:

7213

AN:

250800

AF XY:

0.0292

show subpopulations

Gnomad AFR exome

AF:

0.00683

Gnomad AMR exome

AF:

0.0274

Gnomad ASJ exome

AF:

0.0369

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0198

Gnomad NFE exome

AF:

0.0406

Gnomad OTH exome

AF:

0.0362

GnomAD4 exome

AF:

0.0384

AC:

56182

AN:

1461798

Hom.:

1250

Cov.:

AF XY:

0.0381

AC XY:

27696

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.00729

AC:

244

AN:

33478

American (AMR)

AF:

0.0279

AC:

1248

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0365

AC:

953

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39676

South Asian (SAS)

AF:

0.0169

AC:

1460

AN:

86246

European-Finnish (FIN)

AF:

0.0185

AC:

986

AN:

53410

Middle Eastern (MID)

AF:

0.0293

AC:

169

AN:

5766

European-Non Finnish (NFE)

AF:

0.0442

AC:

49107

AN:

1111972

Other (OTH)

AF:

0.0333

AC:

2014

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

3348

6696

10043

13391

16739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1832

3664

5496

7328

9160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0281

AC:

4272

AN:

152256

Hom.:

Cov.:

AF XY:

0.0263

AC XY:

1958

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00809

AC:

336

AN:

41548

American (AMR)

AF:

0.0341

AC:

521

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0372

AC:

129

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0143

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0193

AC:

205

AN:

10602

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0428

AC:

2914

AN:

68022

Other (OTH)

AF:

0.0360

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

205

410

615

820

1025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0369

Hom.:

435

Bravo

AF:

0.0291

TwinsUK

AF:

0.0415

AC:

154

ALSPAC

AF:

0.0490

AC:

189

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.0437

AC:

376

ExAC

AF:

0.0267

AC:

3245

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0432

EpiControl

AF:

0.0461

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

TET2-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.056

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0036

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PhyloP100

3.9

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.0

REVEL

Benign

0.14

Sift

Uncertain

0.0020

Sift4G

Benign

0.79

Polyphen

0.94

Vest4

0.20

MPC

0.42

ClinPred

0.026

GERP RS

3.1

Varity_R

0.25

gMVP

0.19

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs61744960

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over