4-105237393-G-A

Variant names:

• chr4-105237393-G-A
• rs141975400
• ENST00000305737.6:c.3451G>A

Variant summary

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

The ENST00000305737.6(TET2):​c.3451G>A​(p.Glu1151Lys) 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. 12/18 in silico tools predict 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: 32)
• Consequence: TET2 ENST00000305737.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• 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=0.25785995).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000305737.6. 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.3409+42G>A		intron	N/A	NP_001120680.1
	TET2	NM_017628.4		c.3451G>A	p.Glu1151Lys	missense	Exon 3 of 3	NP_060098.3
	TET2-AS1	NR_126420.1		n.319-59721C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TET2	ENST00000305737.6	TSL:1	c.3451G>A	p.Glu1151Lys	missense	Exon 3 of 3	ENSP00000306705.2
	TET2	ENST00000380013.9	TSL:5 MANE Select	c.3409+42G>A		intron	N/A	ENSP00000369351.4
	TET2	ENST00000513237.5	TSL:1	c.3472+42G>A		intron	N/A	ENSP00000425443.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.7
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.032
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.11	T
Polyphen		0.86	P
Vest4		0.39
MutPred		0.32		Gain of ubiquitination at E1151 (P = 0.0162)
MVP		0.48
ClinPred		0.50	T
GERP RS		5.0
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs141975400; hg19: chr4-106158550;