rs786205226

Variant names:

• chr12-11886025-A-G
• rs786205226
• NM_001987.5:c.1252A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_001987.5(ETV6):​c.1252A>G​(p.Arg418Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R418M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ETV6 NM_001987.5 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.33
• Publications: 12 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a DNA_binding_region ETS (size 81) in uniprot entity ETV6_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_001987.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-11890941-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3064526.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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.1252A>G	p.Arg418Gly	missense splice_region	Exon 7 of 8	NP_001978.1	P41212
	ETV6	NM_001413913.1		c.1249A>G	p.Arg417Gly	missense splice_region	Exon 7 of 8	NP_001400842.1
	ETV6	NM_001413914.1		c.1225A>G	p.Arg409Gly	missense splice_region	Exon 8 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.1252A>G	p.Arg418Gly	missense splice_region	Exon 7 of 8	ENSP00000379658.3	P41212
	ETV6	ENST00000904922.1		c.1249A>G	p.Arg417Gly	missense splice_region	Exon 7 of 8	ENSP00000574981.1
	ETV6	ENST00000904923.1		c.1117A>G	p.Arg373Gly	missense splice_region	Exon 6 of 7	ENSP00000574982.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
1	-	-	Thrombocytopenia 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	33
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.66		Loss of MoRF binding (P = 0.0055)
MVP		0.87
MPC		3.2
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		0.27	Neutral
Varity_R		0.93
gMVP		0.95
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.47		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786205226; hg19: chr12-12038959; COSMIC: COSV56766017;