chr4-105237393-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PVS1_ModerateBS1_Supporting

The ENST00000305737.6(TET2):c.3451G>T(p.Glu1151*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,613,998 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

TET2
ENST00000305737.6 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: 1.72

Publications

10 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: Uncertain_significance. The variant received 1 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0134 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000236 (36/152268) while in subpopulation EAS AF = 0.00636 (33/5188). AF 95% confidence interval is 0.00465. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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
TET2	NM_001127208.3	MANE Select	c.3409+42G>T		intron	N/A	NP_001120680.1
TET2	NM_017628.4		c.3451G>T	p.Glu1151*	stop_gained	Exon 3 of 3	NP_060098.3
TET2-AS1	NR_126420.1		n.319-59721C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TET2	ENST00000305737.6	TSL:1	c.3451G>T	p.Glu1151*	stop_gained	Exon 3 of 3	ENSP00000306705.2
TET2	ENST00000380013.9	TSL:5 MANE Select	c.3409+42G>T		intron	N/A	ENSP00000369351.4
TET2	ENST00000513237.5	TSL:1	c.3472+42G>T		intron	N/A	ENSP00000425443.1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00635

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000617

AC:

154

AN:

249684

AF XY:

0.000598

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00758

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000146

AC:

213

AN:

1461730

Hom.:

Cov.:

AF XY:

0.000142

AC XY:

103

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00416

AC:

165

AN:

39668

South Asian (SAS)

AF:

0.000267

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111946

Other (OTH)

AF:

0.000381

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.000236

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41548

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00636

AC:

AN:

5188

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000229

Hom.:

Bravo

AF:

0.000321

ExAC

AF:

0.000561

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Myelodysplastic syndrome;C5436860:Immunodeficiency 75

Uncertain:1

Jan 01, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

not provided

Uncertain:1

Oct 03, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as a germline variant in three cases with breast adenocarcinoma and one case with stomach adenocarcinoma (Lu et al., 2015); Nonsense variant predicted to result in protein truncation as the last 15 amino acids are lost in a gene for which loss-of-function is not a known mechanism of disease; Reported using an alternate transcript of the gene; This variant is associated with the following publications: (PMID: 30032569, 24728327, 34465723, 32554069, 26689913, 35173275)

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.85

PhyloP100

1.7

Vest4

0.76

GERP RS

5.0

Mutation Taster

=151/49

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over