Genetic Variant ETV6:p.Pro214Leu (chr12-11869601-C-T) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P214Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

ETV6
NM_001987.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 6.89

Publications

42 publications found

Variant links:

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]

ETV6 Gene-Disease associations (from GenCC):

thrombocytopenia 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
acute myeloid leukemia
Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics
hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ETV6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 162222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001987.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ETV6	NM_001987.5	MANE Select	c.641C>T	p.Pro214Leu	missense	Exon 5 of 8	NP_001978.1
ETV6	NM_001413913.1		c.638C>T	p.Pro213Leu	missense	Exon 5 of 8	NP_001400842.1
ETV6	NM_001413914.1		c.614C>T	p.Pro205Leu	missense	Exon 6 of 9	NP_001400843.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ETV6	ENST00000396373.9	TSL:1 MANE Select	c.641C>T	p.Pro214Leu	missense	Exon 5 of 8	ENSP00000379658.3
ETV6	ENST00000904922.1		c.638C>T	p.Pro213Leu	missense	Exon 5 of 8	ENSP00000574981.1
ETV6	ENST00000904923.1		c.506C>T	p.Pro169Leu	missense	Exon 4 of 7	ENSP00000574982.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Thrombocytopenia 5 (6)

not provided (2)

Hereditary cancer-predisposing syndrome (1)

Thrombocytopenia;C0376545:Hematologic neoplasm (1)

Acute myeloid leukemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.038

MetaRNN

Pathogenic

0.78

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

6.9

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.5

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0080

Sift4G

Benign

0.14

Polyphen

0.85

Vest4

0.89

MutPred

0.33

Gain of MoRF binding (P = 0.0613)

MVP

0.26

MPC

0.33

ClinPred

0.69

GERP RS

5.7

Varity_R

0.080

gMVP

0.50

Mutation Taster

=29/71

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over