7-13900829-C-T

Position:

• chr7-13900829-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_004956.5(ETV1):​c.1121G>A​(p.Arg374His) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,453,924 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: 0.000012 (0 hom.)
• Consequence: ETV1 NM_004956.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05

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 Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758
• BS2: High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETV1	NM_004956.5	c.1121G>A	p.Arg374His	missense_variant	13/14	ENST00000430479.6	NP_004947.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETV1	ENST00000430479.6	c.1121G>A	p.Arg374His	missense_variant	13/14	1	NM_004956.5	ENSP00000405327.1
ETV1	ENST00000405358.8	c.1163G>A	p.Arg388His	missense_variant	11/12	5		ENSP00000384085.4
ETV1	ENST00000405218.6	c.1121G>A	p.Arg374His	missense_variant	12/13	5		ENSP00000385551.2
ETV1	ENST00000403685.5	c.1067G>A	p.Arg356His	missense_variant	11/12	1		ENSP00000385686.1
ETV1	ENST00000403527.6	c.1001G>A	p.Arg334His	missense_variant	9/10	1		ENSP00000384138.1
ETV1	ENST00000438956.6	c.947G>A	p.Arg316His	missense_variant	8/9	1		ENSP00000393078.2
ETV1	ENST00000443137.5	n.*81G>A		non_coding_transcript_exon_variant	14/15	2		ENSP00000413836.1
ETV1	ENST00000443137.5	n.*81G>A		3_prime_UTR_variant	14/15	2		ENSP00000413836.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000128 AC: 3 AN: 235122 Hom.: 0 AF XY: 0.0000236 AC XY: 3 AN XY: 127318

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: 0.0000283

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1453924 Hom.: 0 Cov.: 30 AF XY: 0.0000180 AC XY: 13 AN XY: 722504

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: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000166 AC: 2

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

Mar 29, 2024

The c.1121G>A (p.R374H) alteration is located in exon 13 (coding exon 11) of the ETV1 gene. This alteration results from a G to A substitution at nucleotide position 1121, causing the arginine (R) at amino acid position 374 to be replaced by a histidine (H). 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	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D;.;.;.;.;.;.;D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;D;D;D;.
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.9	L;.;.;.;.;.;.;L;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.017	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.058	T;T;D;T;T;T;T;T;T
Polyphen		0.94	P;.;.;D;.;D;.;P;D
Vest4		0.74
MutPred		0.73		.;.;.;.;.;Loss of MoRF binding (P = 0.0154);.;.;.;
MVP		0.54
MPC		0.68
ClinPred		0.90	D
GERP RS		5.8
Varity_R		0.51
gMVP		0.76

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: rs753053339; hg19: chr7-13940454;