7-13906576-T-C

Variant names:

• chr7-13906576-T-C
• rs1782984642
• NM_004956.5:c.964A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004956.5(ETV1):​c.964A>G​(p.Met322Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,609,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ETV1 NM_004956.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16019082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETV1	NM_004956.5	c.964A>G	p.Met322Val	missense_variant	Exon 12 of 14	ENST00000430479.6	NP_004947.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETV1	ENST00000430479.6	c.964A>G	p.Met322Val	missense_variant	Exon 12 of 14	1	NM_004956.5	ENSP00000405327.1
ETV1	ENST00000405358.8	c.1006A>G	p.Met336Val	missense_variant	Exon 10 of 12	5		ENSP00000384085.4
ETV1	ENST00000405218.6	c.964A>G	p.Met322Val	missense_variant	Exon 11 of 13	5		ENSP00000385551.2
ETV1	ENST00000403685.5	c.910A>G	p.Met304Val	missense_variant	Exon 10 of 12	1		ENSP00000385686.1
ETV1	ENST00000403527.6	c.844A>G	p.Met282Val	missense_variant	Exon 8 of 10	1		ENSP00000384138.1
ETV1	ENST00000438956.6	c.790A>G	p.Met264Val	missense_variant	Exon 7 of 9	1		ENSP00000393078.2
ETV1	ENST00000443137.5	n.1028A>G		non_coding_transcript_exon_variant	Exon 13 of 15	2		ENSP00000413836.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457028 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 724608

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.964A>G (p.M322V) alteration is located in exon 12 (coding exon 10) of the ETV1 gene. This alteration results from a A to G substitution at nucleotide position 964, causing the methionine (M) at amino acid position 322 to be replaced by a valine (V). 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	0.063
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.055	T;.;.;.;.;.;.;T;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	0.0077
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	.;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.18	N;.;.;.;.;.;.;N;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.19	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.94	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.67	T;T;T;T;T;T;T;T;T;.
Polyphen		0.0020	B;.;.;B;.;B;.;B;B;.
Vest4		0.20
MutPred		0.22		.;.;.;.;.;Loss of disorder (P = 0.1332);.;.;.;.;
MVP		0.17
MPC		0.14
ClinPred		0.11	T
GERP RS		5.8
Varity_R		0.10
gMVP		0.24

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: rs1782984642; hg19: chr7-13946201;