rs79663578

Variant names:

• chr12-11891471-T-A
• rs79663578
• NM_001987.5:c.*425T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001987.5(ETV6):​c.*425T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 320,020 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ETV6 NM_001987.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0340
• 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), 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETV6	NM_001987.5	MANE Select	c.*425T>A		3_prime_UTR	Exon 8 of 8	NP_001978.1
	ETV6	NM_001413913.1		c.*425T>A		3_prime_UTR	Exon 8 of 8	NP_001400842.1
	ETV6	NM_001413914.1		c.*425T>A		3_prime_UTR	Exon 9 of 9	NP_001400843.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETV6	ENST00000396373.9	TSL:1 MANE Select	c.*425T>A		3_prime_UTR	Exon 8 of 8	ENSP00000379658.3
	ETV6	ENST00000266427.3	TSL:3	c.90-70T>A		intron	N/A	ENSP00000266427.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000125 AC: 4 AN: 320020 Hom.: 0 Cov.: 0 AF XY: 0.00000563 AC XY: 1 AN XY: 177498

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 9544

American (AMR) AF: 0.00 AC: 0 AN: 16802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12346

East Asian (EAS) AF: 0.00 AC: 0 AN: 18766

South Asian (SAS) AF: 0.00 AC: 0 AN: 50054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1878

European-Non Finnish (NFE) AF: 0.0000219 AC: 4 AN: 182466

Other (OTH) AF: 0.00 AC: 0 AN: 17472

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0404278), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.7
DANN	Benign	0.82
PhyloP100		0.034
Mutation Taster		=100/0	polymorphism

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: rs79663578; hg19: chr12-12044405; COSMIC: COSV56766117;