4-105276424-G-T

Variant names:

• chr4-105276424-G-T
• rs587778703
• NM_001127208.3:c.5914G>T

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.5914G>T​(p.Ala1972Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,399,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A1972P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91
• 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=0.08457002).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TET2	NM_001127208.3	MANE Select	c.5914G>T	p.Ala1972Ser	missense	Exon 11 of 11	NP_001120680.1	Q6N021-1
	TET2-AS1	NR_126420.1		n.318+57962C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TET2	ENST00000380013.9	TSL:5 MANE Select	c.5914G>T	p.Ala1972Ser	missense	Exon 11 of 11	ENSP00000369351.4	Q6N021-1
	TET2	ENST00000513237.5	TSL:1	c.5977G>T	p.Ala1993Ser	missense	Exon 11 of 11	ENSP00000425443.1	E7EQS8
	TET2	ENST00000540549.5	TSL:1	c.5914G>T	p.Ala1972Ser	missense	Exon 11 of 11	ENSP00000442788.1	Q6N021-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1399640 Hom.: 0 Cov.: 34 AF XY: 0.00000145 AC XY: 1 AN XY: 690304

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35706

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: 49398

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

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1079008

Other (OTH) AF: 0.00 AC: 0 AN: 58076

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.9
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.031
Sift	Benign	0.069	T
Sift4G	Benign	0.087	T
Polyphen		0.52	P
Vest4		0.23
MutPred		0.27		Gain of phosphorylation at A1993 (P = 0.0417)
MVP		0.23
MPC		0.081
ClinPred		0.14	T
GERP RS		2.3
Varity_R		0.024
gMVP		0.42
Mutation Taster		=94/6	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs587778703; hg19: chr4-106197581;