Genetic Variant NM_001127208.3:c.5333A>G (chr4-105275843-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001127208.3(TET2):c.5333A>G(p.His1778Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0389 in 1,551,808 control chromosomes in the GnomAD database, including 2,446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.078 ( 965 hom., cov: 31)

Exomes 𝑓: 0.035 ( 1481 hom. )

Consequence

TET2
NM_001127208.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.64

Publications

30 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=0.0010084212).

BP6

Variant 4-105275843-A-G is Benign according to our data. Variant chr4-105275843-A-G is described in ClinVar as Benign. ClinVar VariationId is 135289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TET2	NM_001127208.3 link	c.5333A>G	p.His1778Arg	missense_variant	Exon 11 of 11	ENST00000380013.9	NP_001120680.1	Q6N021-1A0A158SIU0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TET2	ENST00000380013.9 link	c.5333A>G	p.His1778Arg	missense_variant	Exon 11 of 11	5	NM_001127208.3	ENSP00000369351.4		Q6N021-1

Frequencies

GnomAD3 genomes

AF:

0.0783

AC:

11913

AN:

152098

Hom.:

966

Cov.:

show subpopulations

Gnomad AFR

AF:

0.206

Gnomad AMI

AF:

0.0275

Gnomad AMR

AF:

0.0402

Gnomad ASJ

AF:

0.0562

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.0286

Gnomad FIN

AF:

0.0217

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0301

Gnomad OTH

AF:

0.0612

GnomAD2 exomes

AF:

0.0367

AC:

5730

AN:

156134

AF XY:

0.0353

show subpopulations

Gnomad AFR exome

AF:

0.208

Gnomad AMR exome

AF:

0.0241

Gnomad ASJ exome

AF:

0.0541

Gnomad EAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.0211

Gnomad NFE exome

AF:

0.0329

Gnomad OTH exome

AF:

0.0320

GnomAD4 exome

AF:

0.0347

AC:

48512

AN:

1399592

Hom.:

1481

Cov.:

AF XY:

0.0341

AC XY:

23530

AN XY:

690304

show subpopulations

African (AFR)

AF:

0.213

AC:

6722

AN:

31600

American (AMR)

AF:

0.0274

AC:

978

AN:

35706

Ashkenazi Jewish (ASJ)

AF:

0.0524

AC:

1320

AN:

25182

East Asian (EAS)

AF:

0.000308

AC:

AN:

35738

South Asian (SAS)

AF:

0.0252

AC:

2000

AN:

79232

European-Finnish (FIN)

AF:

0.0200

AC:

986

AN:

49382

Middle Eastern (MID)

AF:

0.0474

AC:

270

AN:

5698

European-Non Finnish (NFE)

AF:

0.0313

AC:

33771

AN:

1078974

Other (OTH)

AF:

0.0423

AC:

2454

AN:

58080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

2759

5517

8276

11034

13793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1402

2804

4206

5608

7010

<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:

0.0783

AC:

11923

AN:

152216

Hom.:

965

Cov.:

AF XY:

0.0757

AC XY:

5636

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.205

AC:

8519

AN:

41510

American (AMR)

AF:

0.0401

AC:

613

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0562

AC:

195

AN:

3470

East Asian (EAS)

AF:

0.000966

AC:

AN:

5176

South Asian (SAS)

AF:

0.0286

AC:

138

AN:

4826

European-Finnish (FIN)

AF:

0.0217

AC:

230

AN:

10610

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0301

AC:

2046

AN:

68014

Other (OTH)

AF:

0.0606

AC:

128

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

511

1022

1532

2043

2554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<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:

0.0452

Hom.:

1143

Bravo

AF:

0.0852

TwinsUK

AF:

0.0313

AC:

116

ALSPAC

AF:

0.0371

AC:

143

ESP6500AA

AF:

0.184

AC:

255

ESP6500EA

AF:

0.0302

AC:

ExAC

AF:

0.0448

AC:

1145

Asia WGS

AF:

0.0200

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

T;T;T

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.70

T;T;.

MetaRNN

Benign

0.0010

T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.4

.;M;M

PhyloP100

4.6

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.5

N;N;N

REVEL

Benign

0.16

Sift

Uncertain

0.010

D;D;D

Sift4G

Benign

0.33

T;T;T

Polyphen

0.99

D;P;P

Vest4

0.063

MPC

0.41

ClinPred

0.046

GERP RS

5.1

Varity_R

0.18

gMVP

0.35

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over