12-11885968-C-T

Position:

• chr12-11885968-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000396373.9(ETV6):​c.1195C>T​(p.Arg399Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R399H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ETV6 ENST00000396373.9 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.46

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 18 ACMG points.

• PM1: In a helix (size 12) in uniprot entity ETV6_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000396373.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-11885969-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1175817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 12-11885968-C-T is Pathogenic according to our data. Variant chr12-11885968-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 162220.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.1195C>T	p.Arg399Cys	missense_variant	7/8	ENST00000396373.9	NP_001978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETV6	ENST00000396373.9	c.1195C>T	p.Arg399Cys	missense_variant	7/8	1	NM_001987.5	ENSP00000379658	P1
ETV6	ENST00000266427.3	c.34C>T	p.Arg12Cys	missense_variant	1/2	3		ENSP00000266427

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombocytopenia 5 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 24, 2023	Variant summary: ETV6 c.1195C>T (p.Arg399Cys) results in a non-conservative amino acid change located in the Ets domain (IPR000418) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251438 control chromosomes (gnomAD). c.1195C>T has been reported in the literature in individuals affected with Thrombocytopenia and malignancy, and the variant segregated with the disease (examples: Nishi_2021 and Zhang_2015). Published functional studies demonstrate a damaging effect of the variant on protein function. Zhang_2015 demonstrated p.Arg399Cys abrogate DNA binding by ETV6 and failed to repress firefly luciferase reporter constructs containing the MMP3 or PF4 promoter. These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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	GeneDx	Feb 03, 2022	Observed in individuals with a personal history consistent with pathogenic variants in this gene, with segregation in affected individuals from a single family in the literature (Moriyama 2015, Zhang 2015); Published functional studies demonstrate a damaging effect: dominant negative variant leading to mislocalization of protein in cytoplasm and reduced repression of necessary genes for hematopoietic differentiation (Topka 2015, Zhang 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26522332, 26219557, 28637624, 25581430, 26102509, 28555414) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 399 of the ETV6 protein (p.Arg399Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ETV6-related conditions (PMID: 25581430, 26522332). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162220). 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 expected to disrupt ETV6 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ETV6 function (PMID: 25581430, 26102509, 32693409). This variant disrupts the p.Arg399 amino acid residue in ETV6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25581430, 32693409). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Thrombocytopenia;C0376545:Hematologic neoplasm Pathogenic:1

Pathogenic, no assertion criteria provided

research

Akiko Shimamura Lab, Fred Hutchinson Cancer Research Center

Nov 30, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Benign	0.50	N
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.81		Loss of MoRF binding (P = 0.0166);
MVP		0.94
MPC		3.2
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.91
gMVP		0.95

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: rs724159945; hg19: chr12-12038902; COSMIC: COSV56766387;