chr4-105237193-A-C

Position:

• chr4-105237193-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127208.3(TET2):​c.3251A>C​(p.Gln1084Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,614,184 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (10 hom.)
• Consequence: TET2 NM_001127208.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 1.58

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=0.003145367).
• BP6: Variant 4-105237193-A-C is Benign according to our data. Variant chr4-105237193-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 135306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-105237193-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00293 (446/152354) while in subpopulation AMR AF= 0.00392 (60/15306). AF 95% confidence interval is 0.00313. There are 0 homozygotes in gnomad4. There are 250 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TET2	NM_001127208.3	c.3251A>C	p.Gln1084Pro	missense_variant	3/11	ENST00000380013.9
TET2-AS1	NR_126420.1	n.319-59521T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TET2	ENST00000380013.9	c.3251A>C	p.Gln1084Pro	missense_variant	3/11	5	NM_001127208.3	A2

Frequencies

GnomAD3 genomes AF: 0.00293 AC: 446 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00348

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00286 AC: 718 AN: 250770 Hom.: 1 AF XY: 0.00280 AC XY: 380 AN XY: 135534

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00947

Gnomad NFE exome AF: 0.00361

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00334 AC: 4883 AN: 1461830 Hom.: 10 Cov.: 34 AF XY: 0.00321 AC XY: 2338 AN XY: 727220

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00824

Gnomad4 NFE exome AF: 0.00375

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.00293 AC: 446 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.00336 AC XY: 250 AN XY: 74506

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.00348

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00355 Hom.: 3

Bravo AF: 0.00259

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00264 AC: 320

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 04, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	.;T;T;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.60	T;T;T;.;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.0031	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;L;L;.
MutationTaster	Benign	0.94	D;D;D;D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N
REVEL	Benign	0.099
Sift	Uncertain	0.0070	D;D;D;D;D
Sift4G	Benign	0.34	T;T;T;T;T
Polyphen		0.37	B;D;B;B;.
Vest4		0.17
MVP		0.33
MPC		0.086
ClinPred		0.043	T
GERP RS		1.4
Varity_R		0.28
gMVP		0.23

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: rs75056899; hg19: chr4-106158350; COSMIC: COSV104597611; COSMIC: COSV104597611;