3-186080022-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004454.3(ETV5):c.445C>G(p.Leu149Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,547,248 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (31 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (44 hom.)
• Consequence: ETV5 NM_004454.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.03

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027337074).
• BP6: Variant 3-186080022-G-C is Benign according to our data. Variant chr3-186080022-G-C is described in ClinVar as [Benign]. Clinvar id is 780903.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0122 (1848/152070) while in subpopulation AFR AF= 0.0423 (1753/41398). AF 95% confidence interval is 0.0407. There are 31 homozygotes in gnomad4. There are 894 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 1851 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETV5	NM_004454.3	c.445C>G	p.Leu149Val	missense_variant	7/13	ENST00000306376.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETV5	ENST00000306376.10	c.445C>G	p.Leu149Val	missense_variant	7/13	1	NM_004454.3	P1
ETV5-AS1	ENST00000453370.1	n.173-538G>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1851 AN: 151952 Hom.: 31 Cov.: 31

Gnomad AFR AF: 0.0425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00958

GnomAD3 exomes AF: 0.00281 AC: 536 AN: 190758 Hom.: 13 AF XY: 0.00210 AC XY: 221 AN XY: 105412

Gnomad AFR exome AF: 0.0401

Gnomad AMR exome AF: 0.00195

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000902

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000433

Gnomad OTH exome AF: 0.000683

GnomAD4 exome AF: 0.00110 AC: 1532 AN: 1395178 Hom.: 44 Cov.: 36 AF XY: 0.000944 AC XY: 653 AN XY: 691436

Gnomad4 AFR exome AF: 0.0428

Gnomad4 AMR exome AF: 0.00260

Gnomad4 ASJ exome AF: 0.0000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000110

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000239

Gnomad4 OTH exome AF: 0.00284

GnomAD4 genome AF: 0.0122 AC: 1848 AN: 152070 Hom.: 31 Cov.: 31 AF XY: 0.0120 AC XY: 894 AN XY: 74348

Gnomad4 AFR AF: 0.0423

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00948

Alfa AF: 0.00386 Hom.: 3

Bravo AF: 0.0143

ESP6500AA AF: 0.0379 AC: 165

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00400 AC: 485

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.057	T;T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.27	N;N;N
REVEL	Benign	0.060
Sift	Benign	0.16	T;T;D
Sift4G	Benign	1.0	T;T;D
Polyphen		0.0010	B;B;.
Vest4		0.12
MVP		0.40
MPC		0.24
ClinPred		0.0017	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.072
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs78506201; hg19: chr3-185797811;