12-11886025-AGG-GGC

Variant names:

• chr12-11886025-AGG-GGC
• NM_001987.5:c.1252_1253+1delAGGinsGGC
• ETV6 p.Arg418Gly

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001987.5(ETV6):​c.1252_1253+1delAGGinsGGC​(p.Arg418Gly) variant causes a splice donor, missense, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. 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 splice_donor, missense, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

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.1252_1253+1delAGGinsGGC	p.Arg418Gly	splice_donor missense splice_region intron	N/A	NP_001978.1	P41212
	ETV6	NM_001413913.1		c.1249_1250+1delAGGinsGGC	p.Arg417Gly	splice_donor missense splice_region intron	N/A	NP_001400842.1
	ETV6	NM_001413914.1		c.1225_1226+1delAGGinsGGC	p.Arg409Gly	splice_donor missense splice_region intron	N/A	NP_001400843.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETV6	ENST00000396373.9	TSL:1 MANE Select	c.1252_1253+1delAGGinsGGC	p.Arg418Gly	splice_donor missense splice_region intron	N/A	ENSP00000379658.3	P41212
	ETV6	ENST00000904922.1		c.1249_1250+1delAGGinsGGC	p.Arg417Gly	splice_donor missense splice_region intron	N/A	ENSP00000574981.1
	ETV6	ENST00000904923.1		c.1117_1118+1delAGGinsGGC	p.Arg373Gly	splice_donor missense splice_region intron	N/A	ENSP00000574982.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

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

hg19: chr12-12038959;