7-13895870-T-C

Position:

• chr7-13895870-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004956.5(ETV1):​c.1430A>G​(p.Tyr477Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ETV1 NM_004956.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.82

Genes affected

ETV1 (HGNC:3490): (ETS variant transcription factor 1) This gene encodes a member of the ETS (E twenty-six) family of transcription factors. The ETS proteins regulate many target genes that modulate biological processes like cell growth, angiogenesis, migration, proliferation and differentiation. All ETS proteins contain an ETS DNA-binding domain that binds to DNA sequences containing the consensus 5'-CGGA[AT]-3'. The protein encoded by this gene contains a conserved short acidic transactivation domain (TAD) in the N-terminal region, in addition to the ETS DNA-binding domain in the C-terminal region. This gene is involved in chromosomal translocations, which result in multiple fusion proteins including EWS-ETV1 in Ewing sarcoma and at least 10 ETV1 partners (see PMID: 19657377, Table 1) in prostate cancer. In addition to chromosomal rearrangement, this gene is overexpressed in prostate cancer, melanoma and gastrointestinal stromal tumor. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2016]

ETV1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETV1	NM_004956.5	c.1430A>G	p.Tyr477Cys	missense_variant	14/14	ENST00000430479.6	NP_004947.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETV1	ENST00000430479.6	c.1430A>G	p.Tyr477Cys	missense_variant	14/14	1	NM_004956.5	ENSP00000405327.1
ETV1	ENST00000405358.8	c.1472A>G	p.Tyr491Cys	missense_variant	12/12	5		ENSP00000384085.4
ETV1	ENST00000405218.6	c.1430A>G	p.Tyr477Cys	missense_variant	13/13	5		ENSP00000385551.2
ETV1	ENST00000403685.5	c.1376A>G	p.Tyr459Cys	missense_variant	12/12	1		ENSP00000385686.1
ETV1	ENST00000403527.6	c.1310A>G	p.Tyr437Cys	missense_variant	10/10	1		ENSP00000384138.1
ETV1	ENST00000438956.6	c.1256A>G	p.Tyr419Cys	missense_variant	9/9	1		ENSP00000393078.2
ETV1	ENST00000443137.5	n.*390A>G		non_coding_transcript_exon_variant	15/15	2		ENSP00000413836.1
ETV1	ENST00000443137.5	n.*390A>G		3_prime_UTR_variant	15/15	2		ENSP00000413836.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460188 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726314

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2023

The c.1430A>G (p.Y477C) alteration is located in exon 14 (coding exon 12) of the ETV1 gene. This alteration results from a A to G substitution at nucleotide position 1430, causing the tyrosine (Y) at amino acid position 477 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.;.;.;.;.;.;D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;D;D;.
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.;.;M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.2	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;.;D;.;D;D
Vest4		0.88
MutPred		0.40		.;.;.;.;.;Loss of phosphorylation at Y491 (P = 0.0284);.;.;.;
MVP		0.49
MPC		0.70
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.85
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs746999865; hg19: chr7-13935495;