12-11702839-G-A

Variant names:

• chr12-11702839-G-A
• rs2856321
• NM_001987.5:c.34-49611G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001987.5(ETV6):​c.34-49611G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 152,144 control chromosomes in the GnomAD database, including 24,092 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.53 (24092 hom., cov: 33)
• Consequence: ETV6 NM_001987.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 45 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), Ambry Genetics, ClinGen
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETV6	NM_001987.5	c.34-49611G>A		intron_variant	Intron 1 of 7	ENST00000396373.9	NP_001978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETV6	ENST00000396373.9	c.34-49611G>A		intron_variant	Intron 1 of 7	1	NM_001987.5	ENSP00000379658.3
ETV6	ENST00000541426.1	n.218-49611G>A		intron_variant	Intron 1 of 3	4
ETV6	ENST00000544715.1	n.151-13748G>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80258 AN: 152026 Hom.: 24088 Cov.: 33

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.721

Gnomad EAS AF: 0.570

Gnomad SAS AF: 0.577

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.650

Gnomad OTH AF: 0.580

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

GnomAD4 genome AF: 0.528 AC: 80276 AN: 152144 Hom.: 24092 Cov.: 33 AF XY: 0.529 AC XY: 39309 AN XY: 74376

African (AFR) AF: 0.216 AC: 8976 AN: 41524

American (AMR) AF: 0.673 AC: 10284 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.721 AC: 2502 AN: 3470

East Asian (EAS) AF: 0.571 AC: 2948 AN: 5162

South Asian (SAS) AF: 0.578 AC: 2788 AN: 4822

European-Finnish (FIN) AF: 0.629 AC: 6649 AN: 10576

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.650 AC: 44196 AN: 67984

Other (OTH) AF: 0.578 AC: 1219 AN: 2110

Alfa AF: 0.615 Hom.: 94362

Bravo AF: 0.518

Asia WGS AF: 0.524 AC: 1822 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.34
DANN	Benign	0.72
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs2856321; hg19: chr12-11855773;