7-13896016-A-T

Variant names:

• chr7-13896016-A-T
• rs1477637846
• NM_004956.5:c.1284T>A

Variant summary

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

The NM_004956.5(ETV1):​c.1284T>A​(p.Asp428Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,534 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ETV1 NM_004956.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.36

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 rank	MANE	Protein	UniProt
ETV1	NM_004956.5	c.1284T>A	p.Asp428Glu	missense_variant	Exon 14 of 14	ENST00000430479.6	NP_004947.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETV1	ENST00000430479.6	c.1284T>A	p.Asp428Glu	missense_variant	Exon 14 of 14	1	NM_004956.5	ENSP00000405327.1
ETV1	ENST00000405358.8	c.1326T>A	p.Asp442Glu	missense_variant	Exon 12 of 12	5		ENSP00000384085.4
ETV1	ENST00000405218.6	c.1284T>A	p.Asp428Glu	missense_variant	Exon 13 of 13	5		ENSP00000385551.2
ETV1	ENST00000403685.5	c.1230T>A	p.Asp410Glu	missense_variant	Exon 12 of 12	1		ENSP00000385686.1
ETV1	ENST00000403527.6	c.1164T>A	p.Asp388Glu	missense_variant	Exon 10 of 10	1		ENSP00000384138.1
ETV1	ENST00000438956.6	c.1110T>A	p.Asp370Glu	missense_variant	Exon 9 of 9	1		ENSP00000393078.2
ETV1	ENST00000443137.5	n.*244T>A		non_coding_transcript_exon_variant	Exon 15 of 15	2		ENSP00000413836.1
ETV1	ENST00000443137.5	n.*244T>A		3_prime_UTR_variant	Exon 15 of 15	2		ENSP00000413836.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461534 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727026

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1284T>A (p.D428E) alteration is located in exon 14 (coding exon 12) of the ETV1 gene. This alteration results from a T to A substitution at nucleotide position 1284, causing the aspartic acid (D) at amino acid position 428 to be replaced by a glutamic acid (E). 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	0.42
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;.;.;.;.;.;.;D;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	.;D;D;D;D;D;D;D;.
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.;.;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D;D;D
REVEL	Benign	0.25
Sift	Benign	0.065	T;T;T;T;D;T;T;T;T
Sift4G	Benign	0.10	T;T;T;T;T;T;T;T;T
Polyphen		0.85	P;.;.;D;.;D;.;P;D
Vest4		0.60
MutPred		0.37		.;.;.;.;.;Gain of loop (P = 0.1069);.;.;.;
MVP		0.71
MPC		0.60
ClinPred		0.97	D
GERP RS		0.92
Varity_R		0.51
gMVP		0.64

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: rs1477637846; hg19: chr7-13935641;