4-105235006-G-C

Variant names:

• chr4-105235006-G-C
• rs61744960
• NM_001127208.3:c.1064G>C

Variant summary

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

The ENST00000380013.9(TET2):​c.1064G>C​(p.Gly355Ala) 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. 13/22 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. G355D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TET2 ENST00000380013.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.90
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14360306).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000380013.9. 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.1064G>C	p.Gly355Ala	missense	Exon 3 of 11	NP_001120680.1
	TET2	NM_017628.4		c.1064G>C	p.Gly355Ala	missense	Exon 3 of 3	NP_060098.3
	TET2-AS1	NR_126420.1		n.319-57334C>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TET2	ENST00000380013.9	TSL:5 MANE Select	c.1064G>C	p.Gly355Ala	missense	Exon 3 of 11	ENSP00000369351.4
	TET2	ENST00000513237.5	TSL:1	c.1127G>C	p.Gly376Ala	missense	Exon 3 of 11	ENSP00000425443.1
	TET2	ENST00000540549.5	TSL:1	c.1064G>C	p.Gly355Ala	missense	Exon 3 of 11	ENSP00000442788.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.027
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.9
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Benign	0.14	T
Sift4G	Benign	0.29	T
Polyphen		0.13	B
Vest4		0.058
MutPred		0.074		Loss of catalytic residue at G376 (P = 0.0244)
MVP		0.39
MPC		0.15
ClinPred		0.84	D
GERP RS		3.1
Varity_R		0.096
gMVP		0.13
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs61744960; hg19: chr4-106156163;