rs367758008

chr4-105237421-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000305737.6(TET2):c.3479G>A(p.Gly1160Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,613,828 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (17 hom.)
• Consequence: TET2 ENST00000305737.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 0.659

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007689059).
• BP6: Variant 4-105237421-G-A is Benign according to our data. Variant chr4-105237421-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 135328.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000453 (69/152270) while in subpopulation EAS AF= 0.00425 (22/5180). AF 95% confidence interval is 0.00287. There are 2 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TET2	NM_001127208.3	c.3409+70G>A		intron_variant		ENST00000380013.9
TET2-AS1	NR_126420.1	n.319-59749C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TET2	ENST00000380013.9	c.3409+70G>A		intron_variant		5	NM_001127208.3	A2

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152152 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000185 AC: 46 AN: 249120 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135198

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00153

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000192 AC: 281 AN: 1461558 Hom.: 17 Cov.: 33 AF XY: 0.000165 AC XY: 120 AN XY: 727086

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000958

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00363

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152270 Hom.: 2 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74448

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00425

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000499 Hom.: 1

Bravo AF: 0.000397

ESP6500AA AF: 0.000237 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

TET2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 22, 2022

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

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
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	16
Dann	Uncertain	0.98
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D;D;D;D;D;N;N
PROVEAN	Benign	5.6	N
REVEL	Benign	0.072
Sift	Benign	1.0	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.49	P
Vest4		0.35
MVP		0.41
ClinPred		0.011	T
GERP RS		3.0

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: rs367758008; hg19: chr4-106158578;