rs62621450

Positions:

• chr4-105275843-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001127208.3(TET2):​c.5333A>G​(p.His1778Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0389 in 1,551,808 control chromosomes in the GnomAD database, including 2,446 homozygotes. In-silico tool predicts 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 0.078 (965 hom., cov: 31)
  • Exomes 𝑓: 0.035 (1481 hom.)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 4.64

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=0.0010084212).
• BP6: Variant 4-105275843-A-G is Benign according to our data. Variant chr4-105275843-A-G is described in ClinVar as [Benign]. Clinvar id is 135289.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-105275843-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TET2	NM_001127208.3	c.5333A>G	p.His1778Arg	missense_variant	11/11	ENST00000380013.9	NP_001120680.1
TET2-AS1	NR_126420.1	n.318+58543T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TET2	ENST00000380013.9	c.5333A>G	p.His1778Arg	missense_variant	11/11	5	NM_001127208.3	ENSP00000369351	A2
TET2	ENST00000513237.5	c.5396A>G	p.His1799Arg	missense_variant	11/11	1		ENSP00000425443	P4
TET2	ENST00000540549.5	c.5333A>G	p.His1778Arg	missense_variant	11/11	1		ENSP00000442788	A2
TET2	ENST00000265149.9	c.*1657A>G		3_prime_UTR_variant, NMD_transcript_variant	10/10	5		ENSP00000265149

Frequencies

GnomAD3 genomes AF: 0.0783 AC: 11913 AN: 152098 Hom.: 966 Cov.: 31

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0402

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0286

Gnomad FIN AF: 0.0217

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0301

Gnomad OTH AF: 0.0612

GnomAD3 exomes AF: 0.0367 AC: 5730 AN: 156134 Hom.: 250 AF XY: 0.0353 AC XY: 2915 AN XY: 82674

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.0241

Gnomad ASJ exome AF: 0.0541

Gnomad EAS exome AF: 0.00101

Gnomad SAS exome AF: 0.0248

Gnomad FIN exome AF: 0.0211

Gnomad NFE exome AF: 0.0329

Gnomad OTH exome AF: 0.0320

GnomAD4 exome AF: 0.0347 AC: 48512 AN: 1399592 Hom.: 1481 Cov.: 34 AF XY: 0.0341 AC XY: 23530 AN XY: 690304

Gnomad4 AFR exome AF: 0.213

Gnomad4 AMR exome AF: 0.0274

Gnomad4 ASJ exome AF: 0.0524

Gnomad4 EAS exome AF: 0.000308

Gnomad4 SAS exome AF: 0.0252

Gnomad4 FIN exome AF: 0.0200

Gnomad4 NFE exome AF: 0.0313

Gnomad4 OTH exome AF: 0.0423

GnomAD4 genome AF: 0.0783 AC: 11923 AN: 152216 Hom.: 965 Cov.: 31 AF XY: 0.0757 AC XY: 5636 AN XY: 74438

Gnomad4 AFR AF: 0.205

Gnomad4 AMR AF: 0.0401

Gnomad4 ASJ AF: 0.0562

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0286

Gnomad4 FIN AF: 0.0217

Gnomad4 NFE AF: 0.0301

Gnomad4 OTH AF: 0.0606

Alfa AF: 0.0405 Hom.: 397

Bravo AF: 0.0852

TwinsUK AF: 0.0313 AC: 116

ALSPAC AF: 0.0371 AC: 143

ESP6500AA AF: 0.184 AC: 255

ESP6500EA AF: 0.0302 AC: 96

ExAC AF: 0.0448 AC: 1145

Asia WGS AF: 0.0200 AC: 72 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	0.13
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T;T;T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.70	T;T;.
MetaRNN	Benign	0.0010	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.4	.;M;M
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.010	D;D;D
Sift4G	Benign	0.33	T;T;T
Polyphen		0.99	D;P;P
Vest4		0.063
MPC		0.41
ClinPred		0.046	T
GERP RS		5.1
Varity_R		0.18
gMVP		0.35

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs62621450; hg19: chr4-106197000;