chr4-105234171-G-A

Position:

• chr4-105234171-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001127208.3(TET2):​c.229G>A​(p.Asp77Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13207409).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TET2	NM_001127208.3	c.229G>A	p.Asp77Asn	missense_variant	3/11	ENST00000380013.9	NP_001120680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TET2	ENST00000380013.9	c.229G>A	p.Asp77Asn	missense_variant	3/11	5	NM_001127208.3	ENSP00000369351.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2024

The p.D77N variant (also known as c.229G>A), located in coding exon 1 of the TET2 gene, results from a G to A substitution at nucleotide position 229. The aspartic acid at codon 77 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	.;T;T;T;.;.
Eigen	Benign	-0.058
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T;T;T;.;T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.;M;M;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.7	N;N;N;N;N;D
REVEL	Benign	0.080
Sift	Benign	0.086	T;T;T;T;T;T
Sift4G	Uncertain	0.020	D;D;D;D;D;D
Polyphen		0.71	P;B;B;B;.;.
Vest4		0.16
MutPred		0.21		.;Gain of MoRF binding (P = 0.0506);.;.;.;.;
MVP		0.43
MPC		0.13
ClinPred		0.66	D
GERP RS		3.5
Varity_R		0.058
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-106155328;