17-43529634-G-A

Variant names:

• chr17-43529634-G-A
• rs141569304
• NM_001079675.5:c.998C>T

Variant summary

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

The NM_001079675.5(ETV4):​c.998C>T​(p.Pro333Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000775 in 1,613,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: ETV4 NM_001079675.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.16

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 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=0.09051165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETV4	NM_001079675.5	c.998C>T	p.Pro333Leu	missense_variant	Exon 11 of 13	ENST00000319349.10	NP_001073143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETV4	ENST00000319349.10	c.998C>T	p.Pro333Leu	missense_variant	Exon 11 of 13	1	NM_001079675.5	ENSP00000321835.4

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152028 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000917 AC: 23 AN: 250772 Hom.: 0 AF XY: 0.0000664 AC XY: 9 AN XY: 135608

Gnomad AFR exome AF: 0.000864

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000795

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000499 AC: 73 AN: 1461740 Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36 AN XY: 727188

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000423

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152146 Hom.: 0 Cov.: 31 AF XY: 0.000336 AC XY: 25 AN XY: 74366

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.0000654

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: 0.00

Alfa AF: 0.000220 Hom.: 0

Bravo AF: 0.000310

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.998C>T (p.P333L) alteration is located in exon 11 (coding exon 10) of the ETV4 gene. This alteration results from a C to T substitution at nucleotide position 998, causing the proline (P) at amino acid position 333 to be replaced by a leucine (L). 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	0.087
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	.;T;T;.;T;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;.;.;.;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.091	T;T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	2.0	.;M;M;.;.;M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-7.6	D;D;D;D;D;.;.
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D;D;D;D;.;.
Sift4G	Benign	0.15	T;T;T;T;T;T;T
Polyphen		1.0, 0.97	.;D;D;.;D;D;.
Vest4		0.26
MVP		0.74
MPC		1.0
ClinPred		0.33	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.59

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: rs141569304; hg19: chr17-41607002;