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.100C>T(p.Leu34Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,614,044 control chromosomes in the GnomAD database, including 305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L34P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 30 hom., cov: 32)

Exomes 𝑓: 0.017 ( 275 hom. )

Consequence

TET2
NM_001127208.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 0.997

Publications

29 publications found

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: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=0.0051226914).

BP6

Variant 4-105234042-C-T is Benign according to our data. Variant chr4-105234042-C-T is described in ClinVar as Benign. ClinVar VariationId is 135308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0138 (2100/152276) while in subpopulation SAS AF = 0.0189 (91/4822). AF 95% confidence interval is 0.0173. There are 30 homozygotes in GnomAd4. There are 1029 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 30 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.100C>T	p.Leu34Phe	missense	Exon 3 of 11	NP_001120680.1
TET2	NM_017628.4		c.100C>T	p.Leu34Phe	missense	Exon 3 of 3	NP_060098.3
TET2-AS1	NR_126420.1		n.319-56370G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TET2	ENST00000380013.9	TSL:5 MANE Select	c.100C>T	p.Leu34Phe	missense	Exon 3 of 11	ENSP00000369351.4
TET2	ENST00000513237.5	TSL:1	c.163C>T	p.Leu55Phe	missense	Exon 3 of 11	ENSP00000425443.1
TET2	ENST00000540549.5	TSL:1	c.100C>T	p.Leu34Phe	missense	Exon 3 of 11	ENSP00000442788.1

Frequencies

GnomAD3 genomes

AF:

0.0138

AC:

2097

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00350

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.0482

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0186

Gnomad FIN

AF:

0.0201

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0181

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.0156

AC:

3919

AN:

250992

AF XY:

0.0167

show subpopulations

Gnomad AFR exome

AF:

0.00314

Gnomad AMR exome

AF:

0.00706

Gnomad ASJ exome

AF:

0.0439

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0195

Gnomad NFE exome

AF:

0.0191

Gnomad OTH exome

AF:

0.0168

GnomAD4 exome

AF:

0.0171

AC:

24945

AN:

1461768

Hom.:

275

Cov.:

AF XY:

0.0174

AC XY:

12657

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00269

AC:

AN:

33480

American (AMR)

AF:

0.00749

AC:

335

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0442

AC:

1155

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.0167

AC:

1443

AN:

86256

European-Finnish (FIN)

AF:

0.0182

AC:

972

AN:

53404

Middle Eastern (MID)

AF:

0.0241

AC:

139

AN:

5768

European-Non Finnish (NFE)

AF:

0.0177

AC:

19688

AN:

1111960

Other (OTH)

AF:

0.0186

AC:

1123

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1481

2962

4442

5923

7404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

746

1492

2238

2984

3730

<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:

0.0138

AC:

2100

AN:

152276

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

1029

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00351

AC:

146

AN:

41556

American (AMR)

AF:

0.0112

AC:

172

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0482

AC:

167

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.0189

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0201

AC:

213

AN:

10620

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0181

AC:

1232

AN:

68010

Other (OTH)

AF:

0.0180

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

108

216

323

431

539

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0172

Hom.:

Bravo

AF:

0.0123

TwinsUK

AF:

0.0181

AC:

ALSPAC

AF:

0.0218

AC:

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.0190

AC:

163

ExAC

AF:

0.0153

AC:

1853

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0185

EpiControl

AF:

0.0192

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

Eigen

Benign

-0.097

Eigen_PC

Benign

0.046

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0051

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.4

PhyloP100

1.0

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.7

REVEL

Benign

0.037

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.23

Vest4

0.22

MPC

0.18

ClinPred

0.058

GERP RS

4.6

Varity_R

0.29

gMVP

0.31

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs111948941

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