rs587776710

Variant names:

• chr12-11890994-A-AGGG
• rs587776710
• NM_001987.5:c.1307_1308insGGG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_001987.5(ETV6):​c.1307_1308insGGG​(p.His436delinsGlnGly) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ETV6 NM_001987.5 disruptive_inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.38
• Publications: 0 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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• acute myeloid leukemia

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp
• hereditary thrombocytopenia and hematologic cancer predisposition syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001987.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 12-11890994-A-AGGG is Pathogenic according to our data. Variant chr12-11890994-A-AGGG is described in ClinVar as Pathogenic. ClinVar VariationId is 8985.Status of the report is no_assertion_criteria_provided, 0 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.1307_1308insGGG	p.His436delinsGlnGly	disruptive_inframe_insertion	Exon 8 of 8	NP_001978.1	P41212
	ETV6	NM_001413913.1		c.1304_1305insGGG	p.His435delinsGlnGly	disruptive_inframe_insertion	Exon 8 of 8	NP_001400842.1
	ETV6	NM_001413914.1		c.1280_1281insGGG	p.His427delinsGlnGly	disruptive_inframe_insertion	Exon 9 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.1307_1308insGGG	p.His436delinsGlnGly	disruptive_inframe_insertion	Exon 8 of 8	ENSP00000379658.3	P41212
	ETV6	ENST00000904922.1		c.1304_1305insGGG	p.His435delinsGlnGly	disruptive_inframe_insertion	Exon 8 of 8	ENSP00000574981.1
	ETV6	ENST00000904923.1		c.1172_1173insGGG	p.His391delinsGlnGly	disruptive_inframe_insertion	Exon 7 of 7	ENSP00000574982.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Acute myeloid leukemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=36/164	disease causing (ClinVar)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587776710;

hg19: chr12-12043928;