Genetic Variant ENST00000305737.6:c.3479G>A (chr4-105237421-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000305737.6(TET2):c.3479G>A(p.Gly1160Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,613,828 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00045 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 17 hom. )

Consequence

TET2
ENST00000305737.6 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1O:1

Conservation

PhyloP100: 0.659

Publications

7 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007689059).

BP6

Variant 4-105237421-G-A is Benign according to our data. Variant chr4-105237421-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 135328.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000453 (69/152270) while in subpopulation EAS AF = 0.00425 (22/5180). AF 95% confidence interval is 0.00287. There are 2 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000305737.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TET2	NM_001127208.3	MANE Select	c.3409+70G>A		intron	N/A	NP_001120680.1	Q6N021-1
TET2	NM_017628.4		c.3479G>A	p.Gly1160Glu	missense	Exon 3 of 3	NP_060098.3	Q6N021-2
TET2-AS1	NR_126420.1		n.319-59749C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TET2	ENST00000305737.6	TSL:1	c.3479G>A	p.Gly1160Glu	missense	Exon 3 of 3	ENSP00000306705.2	Q6N021-2
TET2	ENST00000380013.9	TSL:5 MANE Select	c.3409+70G>A		intron	N/A	ENSP00000369351.4	Q6N021-1
TET2	ENST00000513237.5	TSL:1	c.3472+70G>A		intron	N/A	ENSP00000425443.1	E7EQS8

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00424

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000185

AC:

AN:

249120

AF XY:

0.000170

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00153

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000192

AC:

281

AN:

1461558

Hom.:

Cov.:

AF XY:

0.000165

AC XY:

120

AN XY:

727086

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33464

American (AMR)

AF:

0.000201

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.000958

AC:

AN:

39662

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111924

Other (OTH)

AF:

0.00363

AC:

219

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000453

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41560

American (AMR)

AF:

0.00164

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00425

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

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:

0.000402

Hom.:

Bravo

AF:

0.000397

ESP6500AA

AF:

0.000237

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000231

AC:

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

TET2-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.070

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.29

M_CAP

Benign

0.018

MetaRNN

Benign

0.0077

MetaSVM

Benign

-0.99

PhyloP100

0.66

PROVEAN

Benign

5.6

REVEL

Benign

0.072

Sift

Benign

1.0

Sift4G

Pathogenic

0.0

Polyphen

0.49

Vest4

0.35

MVP

0.41

ClinPred

0.011

GERP RS

3.0

Mutation Taster

=97/3

polymorphism

(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.

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