12-11754194-C-T

Variant names:

• chr12-11754194-C-T
• rs2051526
• NM_001987.5:c.163+1615C>T

Variant summary

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

The NM_001987.5(ETV6):​c.163+1615C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 152,210 control chromosomes in the GnomAD database, including 1,187 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 0.10 (1187 hom., cov: 32)
• Consequence: ETV6 NM_001987.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.03
• Publications: 4 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETV6	NM_001987.5	c.163+1615C>T		intron_variant	Intron 2 of 7	ENST00000396373.9	NP_001978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETV6	ENST00000396373.9	c.163+1615C>T		intron_variant	Intron 2 of 7	1	NM_001987.5	ENSP00000379658.3
ETV6	ENST00000545027.1	c.79+1615C>T		intron_variant	Intron 1 of 2	5		ENSP00000441463.1
ETV6	ENST00000541426.1	n.347+1615C>T		intron_variant	Intron 2 of 3	4

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15872 AN: 152092 Hom.: 1185 Cov.: 32

Gnomad AFR AF: 0.0299

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0675

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.107

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

GnomAD4 genome AF: 0.104 AC: 15871 AN: 152210 Hom.: 1187 Cov.: 32 AF XY: 0.112 AC XY: 8368 AN XY: 74394

African (AFR) AF: 0.0298 AC: 1239 AN: 41550

American (AMR) AF: 0.0674 AC: 1031 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 389 AN: 3470

East Asian (EAS) AF: 0.300 AC: 1555 AN: 5176

South Asian (SAS) AF: 0.239 AC: 1150 AN: 4820

European-Finnish (FIN) AF: 0.203 AC: 2145 AN: 10562

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8057 AN: 68012

Other (OTH) AF: 0.108 AC: 228 AN: 2116

Alfa AF: 0.108 Hom.: 1595

Bravo AF: 0.0875

Asia WGS AF: 0.247 AC: 855 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.027
DANN	Benign	0.55
PhyloP100		-3.0
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: rs2051526; hg19: chr12-11907128; COSMIC: COSV67148369;