rs111948941

Positions:

• chr4-105234042-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001127208.3(TET2):​c.100C>T​(p.Leu34Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,614,044 control chromosomes in the GnomAD database, including 305 homozygotes. In-silico tool predicts 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 0.014 (30 hom., cov: 32)
  • Exomes 𝑓: 0.017 (275 hom.)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 0.997

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051226914).
• BP6: Variant 4-105234042-C-T is Benign according to our data. Variant chr4-105234042-C-T is described in ClinVar as [Benign]. Clinvar id is 135308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-105234042-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0138 (2100/152276) while in subpopulation SAS AF= 0.0189 (91/4822). AF 95% confidence interval is 0.0173. There are 30 homozygotes in gnomad4. There are 1029 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TET2	NM_001127208.3	c.100C>T	p.Leu34Phe	missense_variant	3/11	ENST00000380013.9
TET2-AS1	NR_126420.1	n.319-56370G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TET2	ENST00000380013.9	c.100C>T	p.Leu34Phe	missense_variant	3/11	5	NM_001127208.3	A2

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2097 AN: 152158 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.00350

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0482

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.0201

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0156 AC: 3919 AN: 250992 Hom.: 46 AF XY: 0.0167 AC XY: 2268 AN XY: 135638

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.00706

Gnomad ASJ exome AF: 0.0439

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0159

Gnomad FIN exome AF: 0.0195

Gnomad NFE exome AF: 0.0191

Gnomad OTH exome AF: 0.0168

GnomAD4 exome AF: 0.0171 AC: 24945 AN: 1461768 Hom.: 275 Cov.: 34 AF XY: 0.0174 AC XY: 12657 AN XY: 727186

Gnomad4 AFR exome AF: 0.00269

Gnomad4 AMR exome AF: 0.00749

Gnomad4 ASJ exome AF: 0.0442

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0167

Gnomad4 FIN exome AF: 0.0182

Gnomad4 NFE exome AF: 0.0177

Gnomad4 OTH exome AF: 0.0186

GnomAD4 genome AF: 0.0138 AC: 2100 AN: 152276 Hom.: 30 Cov.: 32 AF XY: 0.0138 AC XY: 1029 AN XY: 74486

Gnomad4 AFR AF: 0.00351

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.0482

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0189

Gnomad4 FIN AF: 0.0201

Gnomad4 NFE AF: 0.0181

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0180 Hom.: 49

Bravo AF: 0.0123

TwinsUK AF: 0.0181 AC: 67

ALSPAC AF: 0.0218 AC: 84

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0190 AC: 163

ExAC AF: 0.0153 AC: 1853

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0185

EpiControl AF: 0.0192

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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	0.10
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.097
Eigen_PC	Benign	0.046
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.78	T;T;T;.;T;T
MetaRNN	Benign	0.0051	T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.4	M;.;M;M;.;.
MutationTaster	Benign	0.72	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.7	N;N;N;N;N;D
REVEL	Benign	0.037
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.23	B;B;B;B;.;.
Vest4		0.22
MPC		0.18
ClinPred		0.058	T
GERP RS		4.6
Varity_R		0.29
gMVP		0.31

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: rs111948941; hg19: chr4-106155199; COSMIC: COSV54412573;