chr4-105234028-C-G

Position:

• chr4-105234028-C-G

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.86C>G​(p.Pro29Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0319 in 1,613,852 control chromosomes in the GnomAD database, including 2,390 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 0.040 (281 hom., cov: 33)
  • Exomes 𝑓: 0.031 (2109 hom.)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.849

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=0.0011830032).
• BP6: Variant 4-105234028-C-G is Benign according to our data. Variant chr4-105234028-C-G is described in ClinVar as [Benign]. Clinvar id is 135316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TET2	NM_001127208.3	c.86C>G	p.Pro29Arg	missense_variant	3/11	ENST00000380013.9
TET2-AS1	NR_126420.1	n.319-56356G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TET2	ENST00000380013.9	c.86C>G	p.Pro29Arg	missense_variant	3/11	5	NM_001127208.3	A2

Frequencies

GnomAD3 genomes AF: 0.0398 AC: 6048 AN: 152142 Hom.: 278 Cov.: 33

Gnomad AFR AF: 0.0299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0723

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0691

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0435

GnomAD3 exomes AF: 0.0629 AC: 15788 AN: 250816 Hom.: 878 AF XY: 0.0625 AC XY: 8470 AN XY: 135524

Gnomad AFR exome AF: 0.0315

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.0335

Gnomad EAS exome AF: 0.205

Gnomad SAS exome AF: 0.115

Gnomad FIN exome AF: 0.0667

Gnomad NFE exome AF: 0.0181

Gnomad OTH exome AF: 0.0507

GnomAD4 exome AF: 0.0311 AC: 45469 AN: 1461592 Hom.: 2109 Cov.: 34 AF XY: 0.0335 AC XY: 24384 AN XY: 727092

Gnomad4 AFR exome AF: 0.0329

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.0362

Gnomad4 EAS exome AF: 0.203

Gnomad4 SAS exome AF: 0.117

Gnomad4 FIN exome AF: 0.0657

Gnomad4 NFE exome AF: 0.0126

Gnomad4 OTH exome AF: 0.0405

GnomAD4 genome AF: 0.0398 AC: 6057 AN: 152260 Hom.: 281 Cov.: 33 AF XY: 0.0448 AC XY: 3334 AN XY: 74460

Gnomad4 AFR AF: 0.0299

Gnomad4 AMR AF: 0.0730

Gnomad4 ASJ AF: 0.0308

Gnomad4 EAS AF: 0.196

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.0691

Gnomad4 NFE AF: 0.0170

Gnomad4 OTH AF: 0.0430

Alfa AF: 0.0249 Hom.: 83

Bravo AF: 0.0416

TwinsUK AF: 0.0140 AC: 52

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.0300 AC: 132

ESP6500EA AF: 0.0155 AC: 133

ExAC AF: 0.0605 AC: 7343

Asia WGS AF: 0.137 AC: 475 AN: 3478

EpiCase AF: 0.0215

EpiControl AF: 0.0197

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 22. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	.;T;T;T;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.59	T;T;T;.;T;T
MetaRNN	Benign	0.0012	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.;M;M;.;.
MutationTaster	Benign	0.98	P;P;P;P;P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D
REVEL	Benign	0.084
Sift	Uncertain	0.0030	D;D;D;D;D;T
Sift4G	Benign	0.17	T;T;T;T;T;D
Polyphen		0.99	D;P;P;P;.;.
Vest4		0.47
MPC		0.27
ClinPred		0.033	T
GERP RS		4.5
Varity_R		0.23
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12498609; hg19: chr4-106155185; COSMIC: COSV54402572;