4-105275672-T-G

Variant names:

• chr4-105275672-T-G
• rs34402524
• NM_001127208.3:c.5162T>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.5162T>G​(p.Leu1721Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,551,620 control chromosomes in the GnomAD database, including 11,862 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L1721L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1067 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10795 hom.)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 3.37
• Publications: 58 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=0.0013713539).
• BP6: Variant 4-105275672-T-G is Benign according to our data. Variant chr4-105275672-T-G is described in ClinVar as [Benign]. Clinvar id is 135300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TET2	NM_001127208.3	c.5162T>G	p.Leu1721Trp	missense_variant	Exon 11 of 11	ENST00000380013.9	NP_001120680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TET2	ENST00000380013.9	c.5162T>G	p.Leu1721Trp	missense_variant	Exon 11 of 11	5	NM_001127208.3	ENSP00000369351.4

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17593 AN: 152018 Hom.: 1069 Cov.: 32

Gnomad AFR AF: 0.0934

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.0932

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0412

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.121

GnomAD2 exomes AF: 0.116 AC: 18189 AN: 157376 AF XY: 0.118

Gnomad AFR exome AF: 0.0893

Gnomad AMR exome AF: 0.0648

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.0400

Gnomad FIN exome AF: 0.174

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.122 AC: 170522 AN: 1399484 Hom.: 10795 Cov.: 34 AF XY: 0.123 AC XY: 84929 AN XY: 690236

African (AFR) AF: 0.0939 AC: 2968 AN: 31598

American (AMR) AF: 0.0683 AC: 2440 AN: 35708

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3541 AN: 25180

East Asian (EAS) AF: 0.0349 AC: 1248 AN: 35740

South Asian (SAS) AF: 0.122 AC: 9690 AN: 79230

European-Finnish (FIN) AF: 0.169 AC: 8351 AN: 49366

Middle Eastern (MID) AF: 0.175 AC: 995 AN: 5700

European-Non Finnish (NFE) AF: 0.124 AC: 134230 AN: 1078880

Other (OTH) AF: 0.122 AC: 7059 AN: 58082

GnomAD4 genome AF: 0.116 AC: 17594 AN: 152136 Hom.: 1067 Cov.: 32 AF XY: 0.118 AC XY: 8809 AN XY: 74362

African (AFR) AF: 0.0932 AC: 3869 AN: 41504

American (AMR) AF: 0.0932 AC: 1425 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 489 AN: 3472

East Asian (EAS) AF: 0.0411 AC: 212 AN: 5164

South Asian (SAS) AF: 0.109 AC: 525 AN: 4810

European-Finnish (FIN) AF: 0.184 AC: 1946 AN: 10580

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8687 AN: 67992

Other (OTH) AF: 0.122 AC: 258 AN: 2112

Alfa AF: 0.120 Hom.: 3932

Bravo AF: 0.107

TwinsUK AF: 0.120 AC: 446

ALSPAC AF: 0.120 AC: 464

ESP6500AA AF: 0.0968 AC: 134

ESP6500EA AF: 0.135 AC: 429

ExAC AF: 0.118 AC: 3007

Asia WGS AF: 0.0600 AC: 208 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.0067	T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.73	T;T;.
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.90	.;L;L
PhyloP100		3.4
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.030	N;N;N
REVEL	Benign	0.084
Sift	Uncertain	0.0030	D;D;D
Sift4G	Benign	0.23	T;T;T
Polyphen		0.79	P;P;P
Vest4		0.10
MPC		0.35
ClinPred		0.081	T
GERP RS		5.2
Varity_R		0.079
gMVP		0.62
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: rs34402524; hg19: chr4-106196829; COSMIC: COSV54397523;