4-105275794-A-G

Variant names:

• chr4-105275794-A-G
• rs2454206
• NM_001127208.3:c.5284A>G

Variant summary

Our verdict is Benign. The variant received -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1762L) has been classified as Uncertain significance.

• 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:5 O:1
• Conservation: PhyloP100: -0.302
• Publications: 109 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=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 VariationId is 135287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

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.5284A>G	p.Ile1762Val	missense	Exon 11 of 11	NP_001120680.1
	TET2-AS1	NR_126420.1		n.318+58592T>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.5284A>G	p.Ile1762Val	missense	Exon 11 of 11	ENSP00000369351.4
	TET2	ENST00000513237.5	TSL:1	c.5347A>G	p.Ile1783Val	missense	Exon 11 of 11	ENSP00000425443.1
	TET2	ENST00000540549.5	TSL:1	c.5284A>G	p.Ile1762Val	missense	Exon 11 of 11	ENSP00000442788.1

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

GnomAD2 exomes AF: 0.301 AC: 46810 AN: 155570 AF XY: 0.304

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 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

African (AFR) AF: 0.0787 AC: 2486 AN: 31598

American (AMR) AF: 0.241 AC: 8604 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 7981 AN: 25180

East Asian (EAS) AF: 0.217 AC: 7747 AN: 35738

South Asian (SAS) AF: 0.276 AC: 21838 AN: 79224

European-Finnish (FIN) AF: 0.329 AC: 16207 AN: 49238

Middle Eastern (MID) AF: 0.274 AC: 1560 AN: 5698

European-Non Finnish (NFE) AF: 0.380 AC: 409659 AN: 1078862

Other (OTH) AF: 0.321 AC: 18626 AN: 58020

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

African (AFR) AF: 0.0894 AC: 3713 AN: 41520

American (AMR) AF: 0.268 AC: 4089 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1067 AN: 3464

East Asian (EAS) AF: 0.206 AC: 1069 AN: 5180

South Asian (SAS) AF: 0.276 AC: 1329 AN: 4820

European-Finnish (FIN) AF: 0.325 AC: 3434 AN: 10560

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24712 AN: 67994

Other (OTH) AF: 0.253 AC: 534 AN: 2112

Alfa AF: 0.330 Hom.: 44023

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:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.00076	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.30
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.030
Sift	Benign	0.047	D
Sift4G	Benign	0.42	T
Polyphen		0.0010	B
Vest4		0.012
MPC		0.060
ClinPred		0.021	T
GERP RS		-10
Varity_R		0.030
gMVP		0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

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