17-43528665-G-A

Position:

• chr17-43528665-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001079675.5(ETV4):​c.1309C>T​(p.Arg437Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0116 in 1,614,178 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0077 (12 hom., cov: 32)
  • Exomes 𝑓: 0.012 (135 hom.)
• Consequence: ETV4 NM_001079675.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.79

Genes affected

ETV4 (HGNC:3493): (ETS variant transcription factor 4) Enables DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in positive regulation of keratinocyte differentiation and positive regulation of transcription by RNA polymerase II. Located in chromosome and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

DHX8 (HGNC:2749): (DEAH-box helicase 8) This gene is a member of the DEAH box polypeptide family. The encoded protein contains the DEAH (Asp-Glu-Ala-His) motif which is characteristic of all DEAH box proteins, and is thought to function as an ATP-dependent RNA helicase that regulates the release of spliced mRNAs from spliceosomes prior to their export from the nucleus. This protein may be required for the replication of human immunodeficiency virus type 1 (HIV-1). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008488297).
• BP6: Variant 17-43528665-G-A is Benign according to our data. Variant chr17-43528665-G-A is described in ClinVar as [Benign]. Clinvar id is 2647814.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETV4	NM_001079675.5	c.1309C>T	p.Arg437Cys	missense_variant	13/13	ENST00000319349.10	NP_001073143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETV4	ENST00000319349.10	c.1309C>T	p.Arg437Cys	missense_variant	13/13	1	NM_001079675.5	ENSP00000321835	P1

Frequencies

GnomAD3 genomes AF: 0.00774 AC: 1178 AN: 152180 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00761 AC: 1913 AN: 251416 Hom.: 13 AF XY: 0.00749 AC XY: 1018 AN XY: 135902

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.00494

Gnomad NFE exome AF: 0.0131

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0120 AC: 17570 AN: 1461880 Hom.: 135 Cov.: 31 AF XY: 0.0116 AC XY: 8464 AN XY: 727246

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00440

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00125

Gnomad4 FIN exome AF: 0.00517

Gnomad4 NFE exome AF: 0.0145

Gnomad4 OTH exome AF: 0.0118

GnomAD4 genome AF: 0.00773 AC: 1178 AN: 152298 Hom.: 12 Cov.: 32 AF XY: 0.00743 AC XY: 553 AN XY: 74472

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.00654

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00395

Gnomad4 NFE AF: 0.0128

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.0121 Hom.: 16

Bravo AF: 0.00795

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0121 AC: 104

ExAC AF: 0.00756 AC: 918

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0115

EpiControl AF: 0.0126

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

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2022

ETV4: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	.;D;D;.;T;D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;.;.;.;D;D;D
MetaRNN	Benign	0.0085	T;T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.4	.;M;M;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.8	D;D;D;D;D;.;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.022	D;D;D;D;D;.;.
Sift4G	Uncertain	0.046	D;D;D;D;D;D;D
Polyphen		1.0, 0.98	.;D;D;.;D;D;.
Vest4		0.47
MVP		0.87
MPC		1.2
ClinPred		0.068	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.78

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: rs34260468; hg19: chr17-41606033; COSMIC: COSV52251322; COSMIC: COSV52251322;