rs147836249

Positions:

• chr4-105236546-T-G

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.2604T>G​(p.Phe868Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,614,100 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (24 hom.)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.403

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008369237).
• BP6: Variant 4-105236546-T-G is Benign according to our data. Variant chr4-105236546-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 135324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00148 (225/152304) while in subpopulation EAS AF= 0.0168 (87/5190). AF 95% confidence interval is 0.0139. There are 0 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TET2	NM_001127208.3	c.2604T>G	p.Phe868Leu	missense_variant	3/11	ENST00000380013.9	NP_001120680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TET2	ENST00000380013.9	c.2604T>G	p.Phe868Leu	missense_variant	3/11	5	NM_001127208.3	ENSP00000369351.4

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0165

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00933

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00238 AC: 596 AN: 250788 Hom.: 6 AF XY: 0.00222 AC XY: 301 AN XY: 135518

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0126

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00956

Gnomad NFE exome AF: 0.000477

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00120 AC: 1757 AN: 1461796 Hom.: 24 Cov.: 34 AF XY: 0.00117 AC XY: 848 AN XY: 727196

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0220

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.00914

Gnomad4 NFE exome AF: 0.000170

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00148 AC: 225 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74476

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0168

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00933

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00110 Hom.: 3

Bravo AF: 0.000941

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00234 AC: 284

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 26, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	.;T;T;T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.66	T;T;T;.;T
MetaRNN	Benign	0.0084	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.5	M;.;M;M;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.028	D;D;D;D;D
Sift4G	Benign	0.45	T;T;T;T;T
Polyphen		0.43	B;B;B;B;.
Vest4		0.33
MutPred		0.31		.;Gain of disorder (P = 0.1304);.;.;.;
MVP		0.33
MPC		0.12
ClinPred		0.032	T
GERP RS		0.77
Varity_R		0.11
gMVP		0.32

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: rs147836249; hg19: chr4-106157703; COSMIC: COSV54395887; COSMIC: COSV54395887;