4-105275327-G-T

Variant names:

• chr4-105275327-G-T
• rs587778702
• NM_001127208.3:c.4817G>T

Variant summary

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

The NM_001127208.3(TET2):​c.4817G>T​(p.Gly1606Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,570 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G1606A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.16
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.4817G>T	p.Gly1606Val	missense	Exon 11 of 11	NP_001120680.1
	TET2-AS1	NR_126420.1		n.318+59059C>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TET2	ENST00000380013.9	TSL:5 MANE Select	c.4817G>T	p.Gly1606Val	missense	Exon 11 of 11	ENSP00000369351.4
	TET2	ENST00000513237.5	TSL:1	c.4880G>T	p.Gly1627Val	missense	Exon 11 of 11	ENSP00000425443.1
	TET2	ENST00000540549.5	TSL:1	c.4817G>T	p.Gly1606Val	missense	Exon 11 of 11	ENSP00000442788.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399570 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690274

African (AFR) AF: 0.00 AC: 0 AN: 31600

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1079000

Other (OTH) AF: 0.00 AC: 0 AN: 58070

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.2
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.11
Sift	Benign	0.13	T
Sift4G	Benign	0.33	T
Polyphen		0.98	D
Vest4		0.48
MutPred		0.17		Loss of catalytic residue at A1626 (P = 0.05)
MVP		0.53
MPC		0.26
ClinPred		0.89	D
GERP RS		3.4
Varity_R		0.21
gMVP		0.56
Mutation Taster		=96/4	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs587778702; hg19: chr4-106196484;