chr4-105234016-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001127208.3(TET2):​c.74G>T​(p.Cys25Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

TET2
NM_001127208.3 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.69
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.24463174).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TET2NM_001127208.3 linkuse as main transcriptc.74G>T p.Cys25Phe missense_variant 3/11 ENST00000380013.9
TET2-AS1NR_126420.1 linkuse as main transcriptn.319-56344C>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TET2ENST00000380013.9 linkuse as main transcriptc.74G>T p.Cys25Phe missense_variant 3/115 NM_001127208.3 A2Q6N021-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152102
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251050
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135664
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461790
Hom.:
0
Cov.:
33
AF XY:
0.0000151
AC XY:
11
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152102
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74318
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000711
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 27, 2023This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 25 of the TET2 protein (p.Cys25Phe). This variant is present in population databases (rs762289112, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with TET2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.097
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.29
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.070
.;T;T;T;.;.
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.80
T;T;T;.;T;T
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.24
T;T;T;T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Uncertain
2.2
M;.;M;M;.;.
MutationTaster
Benign
0.72
D;D;D;D;D;D;D
PrimateAI
Benign
0.42
T
PROVEAN
Uncertain
-3.7
D;D;D;D;D;D
REVEL
Benign
0.12
Sift
Uncertain
0.0010
D;D;D;D;D;D
Sift4G
Benign
0.067
T;D;D;D;T;T
Polyphen
0.97
D;P;P;P;.;.
Vest4
0.26
MutPred
0.23
.;Gain of relative solvent accessibility (P = 0.0905);.;.;.;.;
MVP
0.60
MPC
0.40
ClinPred
0.97
D
GERP RS
5.4
Varity_R
0.65
gMVP
0.30

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.12
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs762289112; hg19: chr4-106155173; COSMIC: COSV54438611; API