rs62623390

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

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:6O:1

Conservation

PhyloP100: 1.54

Publications

23 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:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0052095056).

BP6

Variant 4-105275613-G-A is Benign according to our data. Variant chr4-105275613-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135296.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 = 0.00379 (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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TET2	NM_001127208.3	MANE Select	c.5103G>A	p.Met1701Ile	missense	Exon 11 of 11	NP_001120680.1
	TET2-AS1	NR_126420.1		n.318+58773C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TET2	ENST00000380013.9	TSL:5 MANE Select	c.5103G>A	p.Met1701Ile	missense	Exon 11 of 11	ENSP00000369351.4
TET2	ENST00000513237.5	TSL:1	c.5166G>A	p.Met1722Ile	missense	Exon 11 of 11	ENSP00000425443.1
TET2	ENST00000540549.5	TSL:1	c.5103G>A	p.Met1701Ile	missense	Exon 11 of 11	ENSP00000442788.1

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

GnomAD2 exomes

AF:

0.00419

AC:

659

AN:

157378

AF XY:

0.00404

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 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

African (AFR)

AF:

0.000791

AC:

AN:

31598

American (AMR)

AF:

0.00185

AC:

AN:

35706

Ashkenazi Jewish (ASJ)

AF:

0.000437

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.000757

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00977

AC:

482

AN:

49356

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00598

AC:

6449

AN:

1078986

Other (OTH)

AF:

0.00358

AC:

208

AN:

58050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

457

915

1372

1830

2287

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

240

480

720

960

1200

<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:

0.00379

AC:

577

AN:

152252

Hom.:

Cov.:

AF XY:

0.00367

AC XY:

273

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00106

AC:

AN:

41540

American (AMR)

AF:

0.00209

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00782

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00601

AC:

409

AN:

68010

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

126

157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00552

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

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

TET2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0081

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0052

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.2

PhyloP100

1.5

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.56

REVEL

Benign

0.052

Sift

Benign

0.12

Sift4G

Benign

0.38

Polyphen

0.0010

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

Mutation Taster

=99/1

polymorphism

(source)

Splicing

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

Publications

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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

Computational scores

Splicing

Publications

Other links and lift over