rs121434637

Variant names:

• chr12-11839202-G-T
• rs121434637
• NM_001987.5:c.226G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-11839202-G-T
• chr12-11839202-G-C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001987.5(ETV6):​c.226G>T​(p.Glu76*) variant causes a stop gained 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. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ETV6 NM_001987.5 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.28
• Publications: 1 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 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-11839202-G-T is Pathogenic according to our data. Variant chr12-11839202-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 8984.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.226G>T	p.Glu76*	stop_gained	Exon 3 of 8	NP_001978.1	P41212
	ETV6	NM_001413913.1		c.223G>T	p.Glu75*	stop_gained	Exon 3 of 8	NP_001400842.1
	ETV6	NM_001413914.1		c.199G>T	p.Glu67*	stop_gained	Exon 4 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.226G>T	p.Glu76*	stop_gained	Exon 3 of 8	ENSP00000379658.3	P41212
	ETV6	ENST00000904922.1		c.223G>T	p.Glu75*	stop_gained	Exon 3 of 8	ENSP00000574981.1
	ETV6	ENST00000904923.1		c.226G>T	p.Glu76*	stop_gained	Exon 3 of 7	ENSP00000574982.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		9.3
Vest4		0.83
GERP RS		5.7
Mutation Taster		=1/199	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: rs121434637; hg19: chr12-11992136; COSMIC: COSV67148966;