rs201642693

chr4-105235227-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_001127208.3(TET2):c.1285G>A(p.Gly429Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000516 in 1,614,014 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 0.763

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05189076).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000532 (81/152158) while in subpopulation NFE AF= 0.00075 (51/67994). AF 95% confidence interval is 0.000586. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TET2	NM_001127208.3	c.1285G>A	p.Gly429Arg	missense_variant	3/11	ENST00000380013.9
TET2-AS1	NR_126420.1	n.319-57555C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TET2	ENST00000380013.9	c.1285G>A	p.Gly429Arg	missense_variant	3/11	5	NM_001127208.3	A2

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000394 AC: 99 AN: 251216 Hom.: 0 AF XY: 0.000435 AC XY: 59 AN XY: 135754

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000625

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000514 AC: 752 AN: 1461856 Hom.: 1 Cov.: 34 AF XY: 0.000505 AC XY: 367 AN XY: 727228

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000611

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74380

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000649 Hom.: 0

Bravo AF: 0.000434

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000395 AC: 48

EpiCase AF: 0.000709

EpiControl AF: 0.000534

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2023	Identified in a bone marrow specimen from an individual with AML in published literature (Li et al., 2016) and in either a bone marrow specimen or in peripheral blood of an unrelated individual with AML (Gaidzik et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22430270, 24728327, 36580013, 26414667) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 09, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 429 of the TET2 protein (p.Gly429Arg). This variant is present in population databases (rs201642693, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with TET2-related conditions. ClinVar contains an entry for this variant (Variation ID: 135318). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Immunodeficiency 75 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 08, 2022

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	17
Dann	Uncertain	1.0
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.85	T;T;T;.;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.052	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.3	M;.;M;M;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.078	T;T;T;T;T
Sift4G	Benign	0.27	T;T;T;T;T
Polyphen		0.93	P;P;P;P;.
Vest4		0.23
MutPred		0.056		.;Gain of helix (P = 0.0199);.;.;.;
MVP		0.30
MPC		0.27
ClinPred		0.022	T
GERP RS		4.3
Varity_R		0.082
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs201642693; hg19: chr4-106156384; COSMIC: COSV54415868; COSMIC: COSV54415868;