rs6843141

Positions:

• chr4-105234594-G-A
• chr4-105234594-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127208.3(TET2):​c.652G>A​(p.Val218Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,613,946 control chromosomes in the GnomAD database, including 4,268 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.10 (1907 hom., cov: 33)
  • Exomes 𝑓: 0.032 (2361 hom.)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.755

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022783577).
• BP6: Variant 4-105234594-G-A is Benign according to our data. Variant chr4-105234594-G-A is described in ClinVar as [Benign]. Clinvar id is 135321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TET2	NM_001127208.3	c.652G>A	p.Val218Met	missense_variant	3/11	ENST00000380013.9	NP_001120680.1
TET2-AS1	NR_126420.1	n.319-56922C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TET2	ENST00000380013.9	c.652G>A	p.Val218Met	missense_variant	3/11	5	NM_001127208.3	ENSP00000369351	A2

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15865 AN: 152066 Hom.: 1899 Cov.: 33

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.0475

Gnomad ASJ AF: 0.0544

Gnomad EAS AF: 0.0665

Gnomad SAS AF: 0.0422

Gnomad FIN AF: 0.0663

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0891

GnomAD3 exomes AF: 0.0511 AC: 12812 AN: 250900 Hom.: 926 AF XY: 0.0466 AC XY: 6317 AN XY: 135582

Gnomad AFR exome AF: 0.293

Gnomad AMR exome AF: 0.0213

Gnomad ASJ exome AF: 0.0501

Gnomad EAS exome AF: 0.0737

Gnomad SAS exome AF: 0.0382

Gnomad FIN exome AF: 0.0693

Gnomad NFE exome AF: 0.0225

Gnomad OTH exome AF: 0.0393

GnomAD4 exome AF: 0.0322 AC: 47041 AN: 1461762 Hom.: 2361 Cov.: 34 AF XY: 0.0317 AC XY: 23052 AN XY: 727170

Gnomad4 AFR exome AF: 0.304

Gnomad4 AMR exome AF: 0.0245

Gnomad4 ASJ exome AF: 0.0504

Gnomad4 EAS exome AF: 0.0782

Gnomad4 SAS exome AF: 0.0376

Gnomad4 FIN exome AF: 0.0638

Gnomad4 NFE exome AF: 0.0192

Gnomad4 OTH exome AF: 0.0502

GnomAD4 genome AF: 0.105 AC: 15914 AN: 152184 Hom.: 1907 Cov.: 33 AF XY: 0.105 AC XY: 7790 AN XY: 74396

Gnomad4 AFR AF: 0.291

Gnomad4 AMR AF: 0.0474

Gnomad4 ASJ AF: 0.0544

Gnomad4 EAS AF: 0.0665

Gnomad4 SAS AF: 0.0421

Gnomad4 FIN AF: 0.0663

Gnomad4 NFE AF: 0.0212

Gnomad4 OTH AF: 0.0882

Alfa AF: 0.0337 Hom.: 764

Bravo AF: 0.111

TwinsUK AF: 0.0181 AC: 67

ALSPAC AF: 0.0228 AC: 88

ESP6500AA AF: 0.284 AC: 1253

ESP6500EA AF: 0.0209 AC: 180

ExAC AF: 0.0548 AC: 6656

EpiCase AF: 0.0206

EpiControl AF: 0.0223

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2020	In silico analysis supports that this missense variant does not alter protein structure/function -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.5
DANN	Benign	0.84
DEOGEN2	Benign	0.0054	.;T;T;T;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.24	T;T;T;.;T
MetaRNN	Benign	0.0023	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.0	N;.;N;N;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.93	N;N;N;N;N
REVEL	Benign	0.051
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.0020	B;B;B;B;.
Vest4		0.091
MPC		0.070
ClinPred		0.00029	T
GERP RS		2.4
Varity_R		0.021
gMVP		0.16

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: rs6843141; hg19: chr4-106155751; COSMIC: COSV54412627; COSMIC: COSV54412627;