7-13931549-G-C

Position:

• chr7-13931549-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004956.5(ETV1):​c.755C>G​(p.Pro252Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ETV1 NM_004956.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.94

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33876222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETV1	NM_004956.5	c.755C>G	p.Pro252Arg	missense_variant	9/14	ENST00000430479.6	NP_004947.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETV1	ENST00000430479.6	c.755C>G	p.Pro252Arg	missense_variant	9/14	1	NM_004956.5	ENSP00000405327.1
ETV1	ENST00000405358.8	c.797C>G	p.Pro266Arg	missense_variant	7/12	5		ENSP00000384085.4
ETV1	ENST00000405218.6	c.755C>G	p.Pro252Arg	missense_variant	8/13	5		ENSP00000385551.2
ETV1	ENST00000403685.5	c.701C>G	p.Pro234Arg	missense_variant	7/12	1		ENSP00000385686.1
ETV1	ENST00000403527.6	c.635C>G	p.Pro212Arg	missense_variant	5/10	1		ENSP00000384138.1
ETV1	ENST00000438956.6	c.581C>G	p.Pro194Arg	missense_variant	4/9	1		ENSP00000393078.2
ETV1	ENST00000443137.5	n.755C>G		non_coding_transcript_exon_variant	9/15	2		ENSP00000413836.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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

May 11, 2022

The c.755C>G (p.P252R) alteration is located in exon 9 (coding exon 7) of the ETV1 gene. This alteration results from a C to G substitution at nucleotide position 755, causing the proline (P) at amino acid position 252 to be replaced by an arginine (R). 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	Benign	0.16
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;.;.;.;.;.;T;.;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.0	N;.;.;.;N;.;.;N;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D;D;D;D;D;D;N
REVEL	Benign	0.19
Sift	Benign	0.18	T;T;T;T;T;T;T;T;T;T;D
Sift4G	Benign	0.24	T;T;T;T;T;T;T;T;T;.;D
Polyphen		0.0010	B;.;.;B;.;P;.;B;B;.;.
Vest4		0.61
MutPred		0.51		.;.;.;.;.;Loss of glycosylation at P266 (P = 0.0113);.;.;.;.;.;
MVP		0.16
MPC		0.18
ClinPred		0.85	D
GERP RS		6.1
Varity_R		0.17
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-13971174; COSMIC: COSV54139204; COSMIC: COSV54139204;