4-105236546-T-G

Variant names:

• chr4-105236546-T-G
• rs147836249
• NM_001127208.3:c.2604T>G

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.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 (★★). Synonymous variant affecting the same amino acid position (i.e. F868F) has been classified 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
• Publications: 30 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=0.008369237).
• BP6: Variant 4-105236546-T-G is Benign according to our data. Variant chr4-105236546-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 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.2604T>G	p.Phe868Leu	missense	Exon 3 of 11	NP_001120680.1
	TET2	NM_017628.4		c.2604T>G	p.Phe868Leu	missense	Exon 3 of 3	NP_060098.3
	TET2-AS1	NR_126420.1		n.319-58874A>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TET2	ENST00000380013.9	TSL:5 MANE Select	c.2604T>G	p.Phe868Leu	missense	Exon 3 of 11	ENSP00000369351.4
	TET2	ENST00000513237.5	TSL:1	c.2667T>G	p.Phe889Leu	missense	Exon 3 of 11	ENSP00000425443.1
	TET2	ENST00000540549.5	TSL:1	c.2604T>G	p.Phe868Leu	missense	Exon 3 of 11	ENSP00000442788.1

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

GnomAD2 exomes AF: 0.00238 AC: 596 AN: 250788 AF XY: 0.00222

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 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

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00192 AC: 86 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0220 AC: 874 AN: 39658

South Asian (SAS) AF: 0.000499 AC: 43 AN: 86258

European-Finnish (FIN) AF: 0.00914 AC: 488 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000170 AC: 189 AN: 1111988

Other (OTH) AF: 0.00121 AC: 73 AN: 60394

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

African (AFR) AF: 0.000168 AC: 7 AN: 41562

American (AMR) AF: 0.000850 AC: 13 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0168 AC: 87 AN: 5190

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.00933 AC: 99 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00119 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

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

May 26, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.40
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Uncertain	0.028	D
Sift4G	Benign	0.45	T
Polyphen		0.43	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
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: rs147836249; hg19: chr4-106157703; COSMIC: COSV54395887; COSMIC: COSV54395887;