NM_001127208.3:c.521C>G

Variant names:

• chr4-105234463-C-G
• rs146031219
• NM_001127208.3:c.521C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001127208.3(TET2):​c.521C>G​(p.Pro174Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P174H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.908
• Publications: 23 publications found

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:41125): (TET2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08321223).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127208.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TET2	NM_001127208.3	MANE Select	c.521C>G	p.Pro174Arg	missense	Exon 3 of 11	NP_001120680.1
	TET2	NM_017628.4		c.521C>G	p.Pro174Arg	missense	Exon 3 of 3	NP_060098.3
	TET2-AS1	NR_126420.1		n.319-56791G>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TET2	ENST00000380013.9	TSL:5 MANE Select	c.521C>G	p.Pro174Arg	missense	Exon 3 of 11	ENSP00000369351.4
	TET2	ENST00000513237.5	TSL:1	c.584C>G	p.Pro195Arg	missense	Exon 3 of 11	ENSP00000425443.1
	TET2	ENST00000540549.5	TSL:1	c.521C>G	p.Pro174Arg	missense	Exon 3 of 11	ENSP00000442788.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250054 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.91
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.086
Sift	Benign	0.091	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.068
MutPred		0.11		Loss of relative solvent accessibility (P = 0.0676)
MVP		0.43
MPC		0.073
ClinPred		0.072	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.13
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs146031219; hg19: chr4-106155620;