7-13931643-G-A

Position:

chr7-13931643-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_004956.5(ETV1):c.661C>T(p.Pro221Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,461,708 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: 0.000032 ( 0 hom. )

Consequence

ETV1
NM_004956.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.35

Variant links:

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 links:

ETV1 (HGNC:):

ETV1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.849

BS2

High AC in GnomAdExome4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETV1	NM_004956.5 linkuse as main transcript	c.661C>T	p.Pro221Ser	missense_variant	9/14	ENST00000430479.6	NP_004947.2	P50549-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ETV1	ENST00000430479.6 linkuse as main transcript	c.661C>T	p.Pro221Ser	missense_variant	9/14	1	NM_004956.5	ENSP00000405327.1	P50549-1
ETV1	ENST00000405358.8 linkuse as main transcript	c.703C>T	p.Pro235Ser	missense_variant	7/12	5		ENSP00000384085.4	B5MCT2
ETV1	ENST00000405218.6 linkuse as main transcript	c.661C>T	p.Pro221Ser	missense_variant	8/13	5		ENSP00000385551.2	P50549-1
ETV1	ENST00000403685.5 linkuse as main transcript	c.607C>T	p.Pro203Ser	missense_variant	7/12	1		ENSP00000385686.1	P50549-2
ETV1	ENST00000403527.6 linkuse as main transcript	c.541C>T	p.Pro181Ser	missense_variant	5/10	1		ENSP00000384138.1	P50549-6
ETV1	ENST00000438956.6 linkuse as main transcript	c.487C>T	p.Pro163Ser	missense_variant	4/9	1		ENSP00000393078.2	P50549-5C9JX69
ETV1	ENST00000443137.5 linkuse as main transcript	n.661C>T		non_coding_transcript_exon_variant	9/15	2		ENSP00000413836.1	F8WEH6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

249286

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135242

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1461708

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000405

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.661C>T (p.P221S) 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 661, causing the proline (P) at amino acid position 221 to be replaced by a serine (S). 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

-0.096

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;.;.;.;.;.;.;T;.;.;.

Eigen

Uncertain

0.61

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

.;D;D;D;D;D;D;D;.;D;D

M_CAP

Benign

0.024

MetaRNN

Pathogenic

0.85

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.5

M;.;.;.;M;.;.;M;.;.;.

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.0

D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.37

Sift

Benign

0.035

D;D;D;D;D;D;D;D;D;D;D

Sift4G

Benign

0.074

T;T;D;T;T;T;T;T;T;.;D

Polyphen

0.15

B;.;.;B;.;P;.;B;B;.;.

Vest4

0.72

MutPred

0.76

.;.;.;.;.;Gain of phosphorylation at P235 (P = 0.0637);.;.;.;.;.;

MVP

0.38

MPC

0.44

ClinPred

0.80

GERP RS

6.1

Varity_R

0.43

gMVP

0.53

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over