4-105275613-G-A

Variant names:

• chr4-105275613-G-A
• rs62623390
• NM_001127208.3:c.5103G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127208.3(TET2):​c.5103G>A​(p.Met1701Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00508 in 1,551,802 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (22 hom.)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 1.54
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052095056).
• BP6: Variant 4-105275613-G-A is Benign according to our data. Variant chr4-105275613-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00379 (577/152252) while in subpopulation NFE AF = 0.00601 (409/68010). AF 95% confidence interval is 0.00553. There are 4 homozygotes in GnomAd4. There are 273 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.5103G>A	p.Met1701Ile	missense	Exon 11 of 11	NP_001120680.1
	TET2-AS1	NR_126420.1		n.318+58773C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TET2	ENST00000380013.9	TSL:5 MANE Select	c.5103G>A	p.Met1701Ile	missense	Exon 11 of 11	ENSP00000369351.4
	TET2	ENST00000513237.5	TSL:1	c.5166G>A	p.Met1722Ile	missense	Exon 11 of 11	ENSP00000425443.1
	TET2	ENST00000540549.5	TSL:1	c.5103G>A	p.Met1701Ile	missense	Exon 11 of 11	ENSP00000442788.1

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 578 AN: 152134 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00782

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00601

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00419 AC: 659 AN: 157378 AF XY: 0.00404

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.000352

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.00647

Gnomad OTH exome AF: 0.00270

GnomAD4 exome AF: 0.00522 AC: 7307 AN: 1399550 Hom.: 22 Cov.: 32 AF XY: 0.00516 AC XY: 3564 AN XY: 690284

African (AFR) AF: 0.000791 AC: 25 AN: 31598

American (AMR) AF: 0.00185 AC: 66 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.000437 AC: 11 AN: 25182

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

South Asian (SAS) AF: 0.000757 AC: 60 AN: 79234

European-Finnish (FIN) AF: 0.00977 AC: 482 AN: 49356

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5700

European-Non Finnish (NFE) AF: 0.00598 AC: 6449 AN: 1078986

Other (OTH) AF: 0.00358 AC: 208 AN: 58050

GnomAD4 genome AF: 0.00379 AC: 577 AN: 152252 Hom.: 4 Cov.: 32 AF XY: 0.00367 AC XY: 273 AN XY: 74454

African (AFR) AF: 0.00106 AC: 44 AN: 41540

American (AMR) AF: 0.00209 AC: 32 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00782 AC: 83 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00601 AC: 409 AN: 68010

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00552 Hom.: 6

Bravo AF: 0.00342

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.00786 AC: 25

ExAC AF: 0.00344 AC: 87

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (2)
-	-	1	TET2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.0081	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.5
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.052
Sift	Benign	0.12	T
Sift4G	Benign	0.38	T
Polyphen		0.0010	B
Vest4		0.18
MutPred		0.20		Loss of disorder (P = 0.0831)
MVP		0.26
MPC		0.078
ClinPred		0.011	T
GERP RS		1.6
Varity_R		0.040
gMVP		0.31
Mutation Taster		=99/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs62623390; hg19: chr4-106196770; COSMIC: COSV105020655;