17-43528676-G-C

Variant names:

• chr17-43528676-G-C
• rs58471799
• NM_001079675.5:c.1298C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001079675.5(ETV4):​c.1298C>G​(p.Pro433Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P433L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ETV4 NM_001079675.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.16
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079675.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETV4	NM_001079675.5	MANE Select	c.1298C>G	p.Pro433Arg	missense	Exon 13 of 13	NP_001073143.1	P43268-1
	ETV4	NM_001369366.2		c.1298C>G	p.Pro433Arg	missense	Exon 13 of 13	NP_001356295.1	P43268-1
	ETV4	NM_001986.4		c.1298C>G	p.Pro433Arg	missense	Exon 13 of 13	NP_001977.1	P43268-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETV4	ENST00000319349.10	TSL:1 MANE Select	c.1298C>G	p.Pro433Arg	missense	Exon 13 of 13	ENSP00000321835.4	P43268-1
	ETV4	ENST00000393664.6	TSL:1	c.1298C>G	p.Pro433Arg	missense	Exon 12 of 12	ENSP00000377273.1	P43268-1
	ETV4	ENST00000591713.5	TSL:1	c.1298C>G	p.Pro433Arg	missense	Exon 13 of 13	ENSP00000465718.1	P43268-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.1	D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.43		Loss of sheet (P = 0.0457)
MVP		0.92
MPC		1.0
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.77
Mutation Taster		=43/57	disease causing

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

Other links and lift over

dbSNP: rs58471799; hg19: chr17-41606044;