rs144386291

chr4-105236541-T-C

Variant summary

Our verdict is Benign. Variant got -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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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:3 O:1
• Conservation: PhyloP100: 6.83

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:):

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TET2	NM_001127208.3	c.2599T>C	p.Tyr867His	missense_variant	3/11	ENST00000380013.9
TET2-AS1	NR_126420.1	n.319-58869A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TET2	ENST00000380013.9	c.2599T>C	p.Tyr867His	missense_variant	3/11	5	NM_001127208.3	A2

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

GnomAD3 exomes AF: 0.00734 AC: 1840 AN: 250772 Hom.: 8 AF XY: 0.00739 AC XY: 1002 AN XY: 135510

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 SAS exome AF: 0.00183

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

Gnomad4 AFR exome AF: 0.00197

Gnomad4 AMR exome AF: 0.00658

Gnomad4 ASJ exome AF: 0.00696

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00225

Gnomad4 FIN exome AF: 0.00202

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.00902

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

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.00628

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.0103 Hom.: 13

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:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TET2: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 28, 2021	- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;D;.;D
MetaRNN	Benign	0.0051	T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M;.;M;M;.
MutationTaster	Benign	0.81	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.7	N;N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Benign	0.50	T;T;T;T;T
Polyphen		1.0	D;D;D;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

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

LitVar

Other links and lift over

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