3-186080103-C-T

Variant names:

• chr3-186080103-C-T
• rs1332934017
• NM_004454.3:c.364G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004454.3(ETV5):​c.364G>A​(p.Ala122Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000759 in 1,317,840 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: ETV5 NM_004454.3 missense, splice_region
• Scores: Splicing: ADA: 0.9770
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.33

Genes affected

ETV5 (HGNC:3494): (ETS variant transcription factor 5) Enables DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Involved in cellular response to oxidative stress; negative regulation of transcription by RNA polymerase II; and positive regulation of transcription by RNA polymerase II. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ETV5-AS1 (HGNC:40222): (ETV5 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETV5	NM_004454.3	c.364G>A	p.Ala122Thr	missense_variant, splice_region_variant	Exon 7 of 13	ENST00000306376.10	NP_004445.1
ETV5-AS1	NR_046594.1	n.173-457C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETV5	ENST00000306376.10	c.364G>A	p.Ala122Thr	missense_variant, splice_region_variant	Exon 7 of 13	1	NM_004454.3	ENSP00000306894.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.59e-7 AC: 1 AN: 1317840 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 643500

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: 9.53e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.364G>A (p.A122T) alteration is located in exon 7 (coding exon 6) of the ETV5 gene. This alteration results from a G to A substitution at nucleotide position 364, causing the alanine (A) at amino acid position 122 to be replaced by a threonine (T). 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	0.24
BayesDel_addAF	Benign	-0.0072	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;T;T;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;D;D;D
M_CAP	Benign	0.0094	T
MetaRNN	Uncertain	0.51	D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.7	N;N;N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0060	D;D;D;D;D
Sift4G	Uncertain	0.059	T;T;T;T;.
Polyphen		0.035	B;B;.;.;.
Vest4		0.68
MutPred		0.71		Gain of phosphorylation at A122 (P = 0.0382);Gain of phosphorylation at A122 (P = 0.0382);Gain of phosphorylation at A122 (P = 0.0382);Gain of phosphorylation at A122 (P = 0.0382);Gain of phosphorylation at A122 (P = 0.0382);
MVP		0.45
MPC		0.26
ClinPred		0.92	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		0.14		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: rs1332934017; hg19: chr3-185797892;