12-11869601-C-T

Variant names:

• chr12-11869601-C-T
• rs724159947
• NM_001987.5:c.641C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV004175267: Experimental studies have demonstrated that this sequence change impacts the function of the ETV6 protein (PMID:25581430, 25807284)." and additional evidence is available in ClinVar. 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 6.89
• Publications: 42 publications found

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), ClinGen, Ambry Genetics
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004175267: Experimental studies have demonstrated that this sequence change impacts the function of the ETV6 protein (PMID: 25581430, 25807284).; SCV005689427: Functional studies have shown that this variant results in a loss of transcriptional repressor activity, as evidenced by luciferase reporter assays, and disrupts normal nuclear localization of the ETV6 protein inhibiting the wild-type ETV6-mediated repression through a dominant-negative mechanism (PMID: 25581430, 25807284).; SCV002065858: Experimental studies have demonstrated that this sequence change impacts the function of the ETV6 protein (PMID: 25581430, 25807284, 32367453).; SCV003440969: Experimental studies have shown that this missense change affects ETV6 function (PMID: 25581430, 25807284).
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETV6	NM_001987.5	MANE Select	c.641C>T	p.Pro214Leu	missense	Exon 5 of 8	NP_001978.1	P41212
	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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETV6	ENST00000396373.9	TSL:1 MANE Select	c.641C>T	p.Pro214Leu	missense	Exon 5 of 8	ENSP00000379658.3	P41212
	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.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Thrombocytopenia 5 (6)
3	-	-	not provided (3)
1	-	-	Hereditary cancer-predisposing syndrome (1)
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	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
PhyloP100		6.9
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
Mutation Taster		=29/71	disease causing (ClinVar)

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

Other links and lift over

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