chr4-105275677-C-T

Variant names:

• chr4-105275677-C-T
• rs146348065
• NM_001127208.3:c.5167C>T

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.5167C>T​(p.Pro1723Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,551,848 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (5 hom., cov: 32)
  • Exomes 𝑓: 0.011 (108 hom.)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.127
• Publications: 38 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=0.00503546).
• BP6: Variant 4-105275677-C-T is Benign according to our data. Variant chr4-105275677-C-T is described in ClinVar as Benign. ClinVar VariationId is 135292.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 = 0.0066 (1005/152272) while in subpopulation NFE AF = 0.0109 (743/68010). AF 95% confidence interval is 0.0103. There are 5 homozygotes in GnomAd4. There are 442 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.5167C>T	p.Pro1723Ser	missense	Exon 11 of 11	NP_001120680.1
	TET2-AS1	NR_126420.1		n.318+58709G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TET2	ENST00000380013.9	TSL:5 MANE Select	c.5167C>T	p.Pro1723Ser	missense	Exon 11 of 11	ENSP00000369351.4
	TET2	ENST00000513237.5	TSL:1	c.5230C>T	p.Pro1744Ser	missense	Exon 11 of 11	ENSP00000425443.1
	TET2	ENST00000540549.5	TSL:1	c.5167C>T	p.Pro1723Ser	missense	Exon 11 of 11	ENSP00000442788.1

Frequencies

GnomAD3 genomes AF: 0.00660 AC: 1004 AN: 152154 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00727 AC: 1144 AN: 157324 AF XY: 0.00714

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.00640

Gnomad ASJ exome AF: 0.00670

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00202

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.00948

GnomAD4 exome AF: 0.0110 AC: 15428 AN: 1399576 Hom.: 108 Cov.: 34 AF XY: 0.0107 AC XY: 7358 AN XY: 690272

African (AFR) AF: 0.00199 AC: 63 AN: 31598

American (AMR) AF: 0.00664 AC: 237 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.00592 AC: 149 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35740

South Asian (SAS) AF: 0.00230 AC: 182 AN: 79236

European-Finnish (FIN) AF: 0.00201 AC: 99 AN: 49360

Middle Eastern (MID) AF: 0.00825 AC: 47 AN: 5700

European-Non Finnish (NFE) AF: 0.0131 AC: 14127 AN: 1078976

Other (OTH) AF: 0.00902 AC: 524 AN: 58078

GnomAD4 genome AF: 0.00660 AC: 1005 AN: 152272 Hom.: 5 Cov.: 32 AF XY: 0.00594 AC XY: 442 AN XY: 74444

African (AFR) AF: 0.00231 AC: 96 AN: 41550

American (AMR) AF: 0.00634 AC: 97 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4822

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10612

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0109 AC: 743 AN: 68010

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00945 Hom.: 17

Bravo AF: 0.00700

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.0123 AC: 39

ExAC AF: 0.00532 AC: 136

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TET2: BP4, BS1, BS2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Apr 28, 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	Benign	0.063
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.89
DANN	Benign	0.71
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.13
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.034
Sift	Benign	0.25	T
Sift4G	Benign	1.0	T
Polyphen		0.13	B
Vest4		0.049
MVP		0.26
MPC		0.089
ClinPred		0.0081	T
GERP RS		1.3
Varity_R		0.049
gMVP		0.54
Mutation Taster		=99/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs146348065; hg19: chr4-106196834; COSMIC: COSV54401122;