Genetic Variant NM_001127208.3:c.5449C>A (chr4-105275959-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001127208.3(TET2):c.5449C>A(p.His1817Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000425 in 1,551,812 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

TET2
NM_001127208.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: 0.494

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 made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058350265).

BP6

Variant 4-105275959-C-A is Benign according to our data. Variant chr4-105275959-C-A is described in ClinVar as [Benign]. Clinvar id is 135293.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00204 (310/152268) while in subpopulation AFR AF= 0.00724 (301/41554). AF 95% confidence interval is 0.00657. There are 1 homozygotes in gnomad4. There are 138 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TET2	NM_001127208.3 link	c.5449C>A	p.His1817Asn	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.5449C>A	p.His1817Asn	missense_variant	Exon 11 of 11	5	NM_001127208.3	ENSP00000369351.4		Q6N021-1

Frequencies

GnomAD3 genomes

AF:

0.00204

AC:

310

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000414

AC:

AN:

157054

Hom.:

AF XY:

0.000385

AC XY:

AN XY:

83020

show subpopulations

Gnomad AFR exome

AF:

0.00644

Gnomad AMR exome

AF:

0.000243

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000220

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000164

Gnomad OTH exome

AF:

0.000226

GnomAD4 exome

AF:

0.000250

AC:

350

AN:

1399544

Hom.:

Cov.:

AF XY:

0.000240

AC XY:

166

AN XY:

690286

show subpopulations

Gnomad4 AFR exome

AF:

0.00807

Gnomad4 AMR exome

AF:

0.000252

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.000551

GnomAD4 genome

AF:

0.00204

AC:

310

AN:

152268

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

138

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00724

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00126

Hom.:

Bravo

AF:

0.00225

ESP6500AA

AF:

0.00723

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000856

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 02, 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

0.078

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.31

DANN

Benign

0.30

DEOGEN2

Benign

0.0098

T;T;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.45

T;T;.

MetaRNN

Benign

0.0058

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.6

.;L;L

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.72

N;N;N

REVEL

Benign

0.021

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.37

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.065

MVP

0.19

MPC

0.077

ClinPred

0.0026

GERP RS

2.3

Varity_R

0.047

gMVP

0.28

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over