rs62623390

chr4-105275613-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127208.3(TET2):c.5103G>A(p.Met1701Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00508 in 1,551,802 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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 0.0038 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (22 hom.)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 1.54

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=0.0052095056).
• BP6: Variant 4-105275613-G-A is Benign according to our data. Variant chr4-105275613-G-A is described in ClinVar as [Benign]. Clinvar id is 135296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-105275613-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00379 (577/152252) while in subpopulation NFE AF= 0.00601 (409/68010). AF 95% confidence interval is 0.00553. There are 4 homozygotes in gnomad4. There are 273 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TET2	NM_001127208.3	c.5103G>A	p.Met1701Ile	missense_variant	11/11	ENST00000380013.9
TET2-AS1	NR_126420.1	n.318+58773C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TET2	ENST00000380013.9	c.5103G>A	p.Met1701Ile	missense_variant	11/11	5	NM_001127208.3	A2
TET2	ENST00000513237.5	c.5166G>A	p.Met1722Ile	missense_variant	11/11	1		P4
TET2	ENST00000540549.5	c.5103G>A	p.Met1701Ile	missense_variant	11/11	1		A2
TET2	ENST00000265149.9	c.*1427G>A		3_prime_UTR_variant, NMD_transcript_variant	10/10	5

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 578 AN: 152134 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00782

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00601

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00419 AC: 659 AN: 157378 Hom.: 3 AF XY: 0.00404 AC XY: 336 AN XY: 83136

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.000352

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000615

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.00647

Gnomad OTH exome AF: 0.00270

GnomAD4 exome AF: 0.00522 AC: 7307 AN: 1399550 Hom.: 22 Cov.: 32 AF XY: 0.00516 AC XY: 3564 AN XY: 690284

Gnomad4 AFR exome AF: 0.000791

Gnomad4 AMR exome AF: 0.00185

Gnomad4 ASJ exome AF: 0.000437

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000757

Gnomad4 FIN exome AF: 0.00977

Gnomad4 NFE exome AF: 0.00598

Gnomad4 OTH exome AF: 0.00358

GnomAD4 genome AF: 0.00379 AC: 577 AN: 152252 Hom.: 4 Cov.: 32 AF XY: 0.00367 AC XY: 273 AN XY: 74454

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00782

Gnomad4 NFE AF: 0.00601

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00580 Hom.: 4

Bravo AF: 0.00342

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.00786 AC: 25

ExAC AF: 0.00344 AC: 87

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	TET2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 24, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

TET2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 24, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	13
Dann	Benign	0.97
DEOGEN2	Benign	0.0081	T;T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.61	T;T;.
MetaRNN	Benign	0.0052	T;T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.56	N;N;N
REVEL	Benign	0.052
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.18
MutPred		0.20		Loss of disorder (P = 0.0831);.;.;
MVP		0.26
MPC		0.078
ClinPred		0.011	T
GERP RS		1.6
Varity_R		0.040
gMVP		0.31

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs62623390; hg19: chr4-106196770; COSMIC: COSV105020655;