4-105236713-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001127208.3(TET2):​c.2771A>G​(p.His924Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00131 in 1,614,148 control chromosomes in the GnomAD database, including 34 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0068 ( 16 hom., cov: 32)
Exomes 𝑓: 0.00073 ( 18 hom. )

Consequence

TET2
NM_001127208.3 missense

Scores

2
16

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 3.95
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]
TET2-AS1 (HGNC:41125): (TET2 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0026900172).
BP6
Variant 4-105236713-A-G is Benign according to our data. Variant chr4-105236713-A-G is described in ClinVar as [Benign]. Clinvar id is 135305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0068 (1036/152334) while in subpopulation AFR AF= 0.0235 (979/41574). AF 95% confidence interval is 0.0223. There are 16 homozygotes in gnomad4. There are 456 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TET2NM_001127208.3 linkc.2771A>G p.His924Arg missense_variant Exon 3 of 11 ENST00000380013.9 NP_001120680.1 Q6N021-1A0A158SIU0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TET2ENST00000380013.9 linkc.2771A>G p.His924Arg missense_variant Exon 3 of 11 5 NM_001127208.3 ENSP00000369351.4 Q6N021-1

Frequencies

GnomAD3 genomes
AF:
0.00679
AC:
1034
AN:
152216
Hom.:
16
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0236
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00281
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:
0.0000441
Gnomad OTH
AF:
0.00526
GnomAD3 exomes
AF:
0.00182
AC:
456
AN:
250726
Hom.:
7
AF XY:
0.00123
AC XY:
166
AN XY:
135460
show subpopulations
Gnomad AFR exome
AF:
0.0255
Gnomad AMR exome
AF:
0.00107
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.000327
GnomAD4 exome
AF:
0.000733
AC:
1072
AN:
1461814
Hom.:
18
Cov.:
34
AF XY:
0.000645
AC XY:
469
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.0271
Gnomad4 AMR exome
AF:
0.00134
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.00147
GnomAD4 genome
AF:
0.00680
AC:
1036
AN:
152334
Hom.:
16
Cov.:
32
AF XY:
0.00612
AC XY:
456
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.0235
Gnomad4 AMR
AF:
0.00281
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00520
Alfa
AF:
0.00117
Hom.:
1
Bravo
AF:
0.00823
ESP6500AA
AF:
0.0229
AC:
101
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00231
AC:
281
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Jan 07, 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:1Other:1
Nov 24, 2021
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.62
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
17
DANN
Benign
0.94
DEOGEN2
Benign
0.0058
.;T;T;T;.
Eigen
Benign
-0.67
Eigen_PC
Benign
-0.51
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.58
T;T;T;.;T
MetaRNN
Benign
0.0027
T;T;T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
0.0
N;.;N;N;.
PrimateAI
Benign
0.30
T
PROVEAN
Benign
0.78
N;N;N;N;N
REVEL
Benign
0.040
Sift
Uncertain
0.0080
D;D;D;D;D
Sift4G
Benign
0.37
T;T;T;T;T
Polyphen
0.0020
B;B;B;B;.
Vest4
0.086
MVP
0.30
MPC
0.084
ClinPred
0.030
T
GERP RS
3.2
Varity_R
0.051
gMVP
0.20

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

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

Other links and lift over

dbSNP: rs34485921; hg19: chr4-106157870; COSMIC: COSV54425023; COSMIC: COSV54425023; API