3-186057125-T-C

Position:

• chr3-186057125-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004454.3(ETV5):​c.1159A>G​(p.Ile387Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ETV5 NM_004454.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETV5	NM_004454.3	c.1159A>G	p.Ile387Val	missense_variant	11/13	ENST00000306376.10	NP_004445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETV5	ENST00000306376.10	c.1159A>G	p.Ile387Val	missense_variant	11/13	1	NM_004454.3	ENSP00000306894.5
ETV5	ENST00000434744.5	c.1159A>G	p.Ile387Val	missense_variant	11/13	1		ENSP00000413755.1
ETV5	ENST00000480706.1	n.333A>G		non_coding_transcript_exon_variant	3/5	3
ETV5	ENST00000433149.1	n.218-4994A>G		intron_variant		5		ENSP00000399707.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Feb 06, 2024

The c.1159A>G (p.I387V) alteration is located in exon 11 (coding exon 10) of the ETV5 gene. This alteration results from a A to G substitution at nucleotide position 1159, causing the isoleucine (I) at amino acid position 387 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	T;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.91	N;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.013	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.71
MutPred		0.79		Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);
MVP		0.84
MPC		3.0
ClinPred		0.88	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-185774914;