4-105236371-A-G

Variant names:

• chr4-105236371-A-G
• rs28555446
• NM_001127208.3:c.2429A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001127208.3(TET2):​c.2429A>G​(p.Gln810Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00062 in 1,614,028 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q810Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (3 hom.)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3 O:1
• Conservation: PhyloP100: 2.92
• Publications: 10 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049034655).
• BP6: Variant 4-105236371-A-G is Benign according to our data. Variant chr4-105236371-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135303.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00264 (402/152340) while in subpopulation AFR AF = 0.00782 (325/41586). AF 95% confidence interval is 0.00712. There are 3 homozygotes in GnomAd4. There are 207 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.2429A>G	p.Gln810Arg	missense	Exon 3 of 11	NP_001120680.1
	TET2	NM_017628.4		c.2429A>G	p.Gln810Arg	missense	Exon 3 of 3	NP_060098.3
	TET2-AS1	NR_126420.1		n.319-58699T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TET2	ENST00000380013.9	TSL:5 MANE Select	c.2429A>G	p.Gln810Arg	missense	Exon 3 of 11	ENSP00000369351.4
	TET2	ENST00000513237.5	TSL:1	c.2492A>G	p.Gln831Arg	missense	Exon 3 of 11	ENSP00000425443.1
	TET2	ENST00000540549.5	TSL:1	c.2429A>G	p.Gln810Arg	missense	Exon 3 of 11	ENSP00000442788.1

Frequencies

GnomAD3 genomes AF: 0.00263 AC: 401 AN: 152222 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00781

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000615 AC: 153 AN: 248798 AF XY: 0.000460

Gnomad AFR exome AF: 0.00706

Gnomad AMR exome AF: 0.000899

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000410 AC: 599 AN: 1461688 Hom.: 3 Cov.: 34 AF XY: 0.000362 AC XY: 263 AN XY: 727128

African (AFR) AF: 0.00777 AC: 260 AN: 33480

American (AMR) AF: 0.000805 AC: 36 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39670

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.000208 AC: 231 AN: 1111980

Other (OTH) AF: 0.000960 AC: 58 AN: 60394

GnomAD4 genome AF: 0.00264 AC: 402 AN: 152340 Hom.: 3 Cov.: 32 AF XY: 0.00278 AC XY: 207 AN XY: 74498

African (AFR) AF: 0.00782 AC: 325 AN: 41586

American (AMR) AF: 0.00458 AC: 70 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000543 Hom.: 1

Bravo AF: 0.00303

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000634 AC: 77

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.9
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.078
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.026	D
Polyphen		0.10	B
Vest4		0.12
MVP		0.20
MPC		0.080
ClinPred		0.049	T
GERP RS		4.6
Varity_R		0.19
gMVP		0.28
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs28555446; hg19: chr4-106157528; COSMIC: COSV99035900;