4-105275794-A-G

Position:

• chr4-105275794-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127208.3(TET2):​c.5284A>G​(p.Ile1762Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 1,551,382 control chromosomes in the GnomAD database, including 96,786 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.27 (6380 hom., cov: 31)
  • Exomes 𝑓: 0.35 (90406 hom.)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.302

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.6285005E-4).
• BP6: Variant 4-105275794-A-G is Benign according to our data. Variant chr4-105275794-A-G is described in ClinVar as [Benign]. Clinvar id is 135287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-105275794-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TET2	NM_001127208.3	c.5284A>G	p.Ile1762Val	missense_variant	11/11	ENST00000380013.9	NP_001120680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TET2	ENST00000380013.9	c.5284A>G	p.Ile1762Val	missense_variant	11/11	5	NM_001127208.3	ENSP00000369351.4

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40376 AN: 152002 Hom.: 6381 Cov.: 31

Gnomad AFR AF: 0.0896

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.257

GnomAD3 exomes AF: 0.301 AC: 46810 AN: 155570 Hom.: 7468 AF XY: 0.304 AC XY: 25060 AN XY: 82432

Gnomad AFR exome AF: 0.0879

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.315

Gnomad EAS exome AF: 0.212

Gnomad SAS exome AF: 0.281

Gnomad FIN exome AF: 0.333

Gnomad NFE exome AF: 0.366

Gnomad OTH exome AF: 0.316

GnomAD4 exome AF: 0.354 AC: 494708 AN: 1399260 Hom.: 90406 Cov.: 49 AF XY: 0.352 AC XY: 243018 AN XY: 690134

Gnomad4 AFR exome AF: 0.0787

Gnomad4 AMR exome AF: 0.241

Gnomad4 ASJ exome AF: 0.317

Gnomad4 EAS exome AF: 0.217

Gnomad4 SAS exome AF: 0.276

Gnomad4 FIN exome AF: 0.329

Gnomad4 NFE exome AF: 0.380

Gnomad4 OTH exome AF: 0.321

GnomAD4 genome AF: 0.265 AC: 40368 AN: 152122 Hom.: 6380 Cov.: 31 AF XY: 0.262 AC XY: 19463 AN XY: 74342

Gnomad4 AFR AF: 0.0894

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.308

Gnomad4 EAS AF: 0.206

Gnomad4 SAS AF: 0.276

Gnomad4 FIN AF: 0.325

Gnomad4 NFE AF: 0.363

Gnomad4 OTH AF: 0.253

Alfa AF: 0.339 Hom.: 23469

Bravo AF: 0.254

TwinsUK AF: 0.388 AC: 1440

ALSPAC AF: 0.388 AC: 1496

ESP6500AA AF: 0.0896 AC: 124

ESP6500EA AF: 0.373 AC: 1188

ExAC AF: 0.272 AC: 6822

Asia WGS AF: 0.237 AC: 827 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 54% of patients studied by a panel of primary immunodeficiencies. Number of patients: 51. Only high quality variants are reported. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.20
DANN	Benign	0.59
DEOGEN2	Benign	0.0059	T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.46	T;T;.
MetaRNN	Benign	0.00076	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.4	.;L;L
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.060	N;N;N
REVEL	Benign	0.030
Sift	Benign	0.047	D;D;D
Sift4G	Benign	0.42	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.012
MPC		0.060
ClinPred		0.021	T
GERP RS		-10
Varity_R		0.030
gMVP		0.18

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2454206; hg19: chr4-106196951; COSMIC: COSV54396998;