rs724159947

Positions:

• chr12-11869601-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001987.5(ETV6):​c.641C>T​(p.Pro214Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ETV6 NM_001987.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 6.89

Genes affected

ETV6 (HGNC:3495): (ETS variant transcription factor 6) This gene encodes an ETS family transcription factor. The product of this gene contains two functional domains: a N-terminal pointed (PNT) domain that is involved in protein-protein interactions with itself and other proteins, and a C-terminal DNA-binding domain. Gene knockout studies in mice suggest that it is required for hematopoiesis and maintenance of the developing vascular network. This gene is known to be involved in a large number of chromosomal rearrangements associated with leukemia and congenital fibrosarcoma. [provided by RefSeq, Sep 2008]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783
• PP5: Variant 12-11869601-C-T is Pathogenic according to our data. Variant chr12-11869601-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETV6	NM_001987.5	c.641C>T	p.Pro214Leu	missense_variant	5/8	ENST00000396373.9	NP_001978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETV6	ENST00000396373.9	c.641C>T	p.Pro214Leu	missense_variant	5/8	1	NM_001987.5	ENSP00000379658	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombocytopenia 5 Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 20, 2023	The ETV6 c.641C>T variant is classified as Likely Pathogenic (PS3_Supporting, PS4_Moderate, PM2, PP1_Moderate) The ETV6 c.641C>T variant is a single nucleotide change in exon 5/8 of the ETV6 gene, which is predicted to change the amino acid proline at position 214 in the protein to leucine. Experimental studies have demonstrated that this sequence change impacts the function of the ETV6 protein (PMID: 25581430, 25807284). The p.Pro214Leu variant affects a highly conserved amino acid residue located in a linker inhibitory domain (amino acids 127–331) that indirectly promotes DNA binding (PS3_Supporting). The variant has been reported in multiple unrelated proband(s) with a clinical presentation of Thrombocytopenia. In addition, this variant has been reported in a patient subsequently developing a T cell/myloid mixed phenotype acute leukemia (MPAL) (PMID:25581430) (PS4_Moderate).This variant is absent from population databases (PM2). This variant co-segregates with disease demonstrated in PMID:27666367 which noted four generations of affected family members. (PP1_moderate). The variant has been reported in dbSNP (rs724159947) and in the HGMD database: CM150819. It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 162222). -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Oct 14, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 31, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 24, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 214 of the ETV6 protein (p.Pro214Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial thrombocytopenia with leukemia (PMID: 25581430, 25807284, 31704777, 33768492). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162222). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ETV6 protein function. Experimental studies have shown that this missense change affects ETV6 function (PMID: 25581430, 25807284). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 12, 2021	DNA sequence analysis of the ETV6 gene demonstrated a sequence change, c.641C>T, in exon 5 that results in an amino acid change, p.Pro214Leu. This pathogenic sequence change has previously been described in multiple individuals with ETV6-related thrombocytopenia and has been shown to segregate with disease in at least two families (PMID: 25581430, 25807284, 27663637, 31704777, 32367453). Additionally, experimental studies have demonstrated that this sequence change impacts the function of the ETV6 protein (PMID: 25581430, 25807284, 32367453). This sequence change has not been described in population databases including gnomAD (dbSNP rs724159947). The p.Pro214Leu change affects a highly conserved amino acid residue located in a domain of the ETV6 protein that is known to be functional. The p.Pro214Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Collectively these evidences suggest that, the c.641C>T change is pathogenic. -

Thrombocytopenia;C0376545:Hematologic neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Akiko Shimamura Lab, Fred Hutchinson Cancer Research Center

Nov 30, 2014

- -

Acute myeloid leukemia Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.14	T
Polyphen		0.85	P
Vest4		0.89
MutPred		0.33		Gain of MoRF binding (P = 0.0613);
MVP		0.26
MPC		0.33
ClinPred		0.69	D
GERP RS		5.7
Varity_R		0.080
gMVP		0.50

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: rs724159947; hg19: chr12-12022535; COSMIC: COSV67147991;