rs146348065

chr4-105275677-C-T

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.5167C>T(p.Pro1723Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,551,848 control chromosomes in the GnomAD database, including 113 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 0.0066 (5 hom., cov: 32)
  • Exomes 𝑓: 0.011 (108 hom.)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.127

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=0.00503546).
• BP6: Variant 4-105275677-C-T is Benign according to our data. Variant chr4-105275677-C-T is described in ClinVar as [Benign]. Clinvar id is 135292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0066 (1005/152272) while in subpopulation NFE AF= 0.0109 (743/68010). AF 95% confidence interval is 0.0103. There are 5 homozygotes in gnomad4. There are 442 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TET2	NM_001127208.3	c.5167C>T	p.Pro1723Ser	missense_variant	11/11	ENST00000380013.9
TET2-AS1	NR_126420.1	n.318+58709G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TET2	ENST00000380013.9	c.5167C>T	p.Pro1723Ser	missense_variant	11/11	5	NM_001127208.3	A2
TET2	ENST00000513237.5	c.5230C>T	p.Pro1744Ser	missense_variant	11/11	1		P4
TET2	ENST00000540549.5	c.5167C>T	p.Pro1723Ser	missense_variant	11/11	1		A2
TET2	ENST00000265149.9	c.*1491C>T		3_prime_UTR_variant, NMD_transcript_variant	10/10	5

Frequencies

GnomAD3 genomes AF: 0.00660 AC: 1004 AN: 152154 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00727 AC: 1144 AN: 157324 Hom.: 5 AF XY: 0.00714 AC XY: 593 AN XY: 83048

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.00640

Gnomad ASJ exome AF: 0.00670

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00193

Gnomad FIN exome AF: 0.00202

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.00948

GnomAD4 exome AF: 0.0110 AC: 15428 AN: 1399576 Hom.: 108 Cov.: 34 AF XY: 0.0107 AC XY: 7358 AN XY: 690272

Gnomad4 AFR exome AF: 0.00199

Gnomad4 AMR exome AF: 0.00664

Gnomad4 ASJ exome AF: 0.00592

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00230

Gnomad4 FIN exome AF: 0.00201

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.00902

GnomAD4 genome AF: 0.00660 AC: 1005 AN: 152272 Hom.: 5 Cov.: 32 AF XY: 0.00594 AC XY: 442 AN XY: 74444

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.0101 Hom.: 12

Bravo AF: 0.00700

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.0123 AC: 39

ExAC AF: 0.00532 AC: 136

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 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	Feb 01, 2024	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	Apr 28, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.89
Dann	Benign	0.71
DEOGEN2	Benign	0.013	T;T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.71	T;T;.
MetaRNN	Benign	0.0050	T;T;T
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Benign	0.034
Sift	Benign	0.25	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.13	B;B;B
Vest4		0.049
MVP		0.26
MPC		0.089
ClinPred		0.0081	T
GERP RS		1.3
Varity_R		0.049
gMVP		0.54

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs146348065; hg19: chr4-106196834; COSMIC: COSV54401122;