chr7-13931546-G-A

Position:

• chr7-13931546-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004956.5(ETV1):​c.758C>T​(p.Pro253Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 5.86

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETV1	NM_004956.5	c.758C>T	p.Pro253Leu	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.758C>T	p.Pro253Leu	missense_variant	9/14	1	NM_004956.5	ENSP00000405327	P1

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

Apr 04, 2023

The c.758C>T (p.P253L) alteration is located in exon 9 (coding exon 7) of the ETV1 gene. This alteration results from a C to T substitution at nucleotide position 758, causing the proline (P) at amino acid position 253 to be replaced by a leucine (L). 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	0.12
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;.;.;.;.;.;T;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L;.;.;.;L;.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0070	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T;T;.;D
Polyphen		0.78	P;.;.;P;.;P;.;P;P;.;.
Vest4		0.58
MutPred		0.63		.;.;.;.;.;Loss of disorder (P = 0.0085);.;.;.;.;.;
MVP		0.31
MPC		0.29
ClinPred		0.95	D
GERP RS		6.1
Varity_R		0.22
gMVP		0.32

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: chr7-13971171;