rs144386291

Variant names:

• chr4-105236541-T-C
• rs144386291
• NM_001127208.3:c.2599T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127208.3(TET2):​c.2599T>C​(p.Tyr867His) variant causes a missense change. The variant allele was found at a frequency of 0.0105 in 1,614,090 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y867C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0066 (5 hom., cov: 32)
  • Exomes 𝑓: 0.011 (114 hom.)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 6.83
• Publications: 46 publications found

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-AS1 (HGNC:41125): (TET2 antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.005108267).
• BP6: Variant 4-105236541-T-C is Benign according to our data. Variant chr4-105236541-T-C is described in ClinVar as Benign. ClinVar VariationId is 135323.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 = 0.00664 (1012/152296) while in subpopulation NFE AF = 0.011 (749/68018). AF 95% confidence interval is 0.0104. There are 5 homozygotes in GnomAd4. There are 444 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.2599T>C	p.Tyr867His	missense	Exon 3 of 11	NP_001120680.1
	TET2	NM_017628.4		c.2599T>C	p.Tyr867His	missense	Exon 3 of 3	NP_060098.3
	TET2-AS1	NR_126420.1		n.319-58869A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TET2	ENST00000380013.9	TSL:5 MANE Select	c.2599T>C	p.Tyr867His	missense	Exon 3 of 11	ENSP00000369351.4
	TET2	ENST00000513237.5	TSL:1	c.2662T>C	p.Tyr888His	missense	Exon 3 of 11	ENSP00000425443.1
	TET2	ENST00000540549.5	TSL:1	c.2599T>C	p.Tyr867His	missense	Exon 3 of 11	ENSP00000442788.1

Frequencies

GnomAD3 genomes AF: 0.00664 AC: 1011 AN: 152178 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00734 AC: 1840 AN: 250772 AF XY: 0.00739

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00631

Gnomad ASJ exome AF: 0.00755

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.00932

GnomAD4 exome AF: 0.0110 AC: 16012 AN: 1461794 Hom.: 114 Cov.: 34 AF XY: 0.0106 AC XY: 7692 AN XY: 727192

African (AFR) AF: 0.00197 AC: 66 AN: 33480

American (AMR) AF: 0.00658 AC: 294 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00696 AC: 182 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00225 AC: 194 AN: 86258

European-Finnish (FIN) AF: 0.00202 AC: 108 AN: 53412

Middle Eastern (MID) AF: 0.00832 AC: 48 AN: 5768

European-Non Finnish (NFE) AF: 0.0131 AC: 14575 AN: 1111986

Other (OTH) AF: 0.00902 AC: 545 AN: 60394

GnomAD4 genome AF: 0.00664 AC: 1012 AN: 152296 Hom.: 5 Cov.: 32 AF XY: 0.00596 AC XY: 444 AN XY: 74468

African (AFR) AF: 0.00231 AC: 96 AN: 41572

American (AMR) AF: 0.00628 AC: 96 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4826

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0110 AC: 749 AN: 68018

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.0101 Hom.: 38

Bravo AF: 0.00710

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.0124 AC: 107

ExAC AF: 0.00689 AC: 837

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0125

EpiControl AF: 0.0137

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TET2: BS1, BS2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1 Other:1

Apr 28, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.50	T
Polyphen		1.0	D
Vest4		0.63
MVP		0.46
MPC		0.46
ClinPred		0.017	T
GERP RS		5.8
Varity_R		0.22
gMVP		0.51
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs144386291; hg19: chr4-106157698; COSMIC: COSV54409754; COSMIC: COSV54409754;