chr17-43529652-C-T

Variant names:

• chr17-43529652-C-T
• rs750731483
• NM_001079675.5:c.980G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001079675.5(ETV4):​c.980G>A​(p.Gly327Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ETV4 NM_001079675.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.61
• Publications: 2 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25690526).

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.980G>A	p.Gly327Asp	missense	Exon 11 of 13	NP_001073143.1	P43268-1
	ETV4	NM_001369366.2		c.980G>A	p.Gly327Asp	missense	Exon 11 of 13	NP_001356295.1	P43268-1
	ETV4	NM_001986.4		c.980G>A	p.Gly327Asp	missense	Exon 11 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.980G>A	p.Gly327Asp	missense	Exon 11 of 13	ENSP00000321835.4	P43268-1
	ETV4	ENST00000393664.6	TSL:1	c.980G>A	p.Gly327Asp	missense	Exon 10 of 12	ENSP00000377273.1	P43268-1
	ETV4	ENST00000591713.5	TSL:1	c.980G>A	p.Gly327Asp	missense	Exon 11 of 13	ENSP00000465718.1	P43268-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249646 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460792 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726672

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111404

Other (OTH) AF: 0.00 AC: 0 AN: 60342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.15
Sift	Uncertain	0.010	D
Sift4G	Benign	0.12	T
Polyphen		0.70	P
Vest4		0.32
MutPred		0.62		Loss of methylation at K322 (P = 0.1057)
MVP		0.46
MPC		0.67
ClinPred		0.60	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs750731483; hg19: chr17-41607020; COSMIC: COSV52255249; COSMIC: COSV52255249;