rs2271959

Variant names:

• chr17-43545372-G-T
• rs2271959
• NM_001079675.5:c.61-5C>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_001079675.5(ETV4):​c.61-5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,577,064 control chromosomes in the GnomAD database, including 72,834 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5645 hom., cov: 31)
  • Exomes 𝑓: 0.30 (67189 hom.)
• Consequence: ETV4 NM_001079675.5 splice_region, intron
• Scores: Splicing: ADA: 0.9988
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.35
• Publications: 19 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: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 17-43545372-G-T is Benign according to our data. Variant chr17-43545372-G-T is described in ClinVar as Benign. ClinVar VariationId is 1295936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETV4	NM_001079675.5	MANE Select	c.61-5C>A		splice_region intron	N/A	NP_001073143.1
	ETV4	NM_001369366.2		c.61-5C>A		splice_region intron	N/A	NP_001356295.1
	ETV4	NM_001986.4		c.61-5C>A		splice_region intron	N/A	NP_001977.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETV4	ENST00000319349.10	TSL:1 MANE Select	c.61-5C>A		splice_region intron	N/A	ENSP00000321835.4
	ETV4	ENST00000393664.6	TSL:1	c.61-5C>A		splice_region intron	N/A	ENSP00000377273.1
	ETV4	ENST00000591713.5	TSL:1	c.61-5C>A		splice_region intron	N/A	ENSP00000465718.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39009 AN: 152010 Hom.: 5646 Cov.: 31

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.254

GnomAD2 exomes AF: 0.299 AC: 58046 AN: 193856 AF XY: 0.304

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.248

Gnomad ASJ exome AF: 0.299

Gnomad EAS exome AF: 0.312

Gnomad FIN exome AF: 0.396

Gnomad NFE exome AF: 0.324

Gnomad OTH exome AF: 0.290

GnomAD4 exome AF: 0.304 AC: 433781 AN: 1424936 Hom.: 67189 Cov.: 34 AF XY: 0.305 AC XY: 214815 AN XY: 705110

African (AFR) AF: 0.117 AC: 3835 AN: 32826

American (AMR) AF: 0.241 AC: 9582 AN: 39750

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 7364 AN: 25096

East Asian (EAS) AF: 0.364 AC: 13931 AN: 38276

South Asian (SAS) AF: 0.278 AC: 22733 AN: 81632

European-Finnish (FIN) AF: 0.384 AC: 19635 AN: 51096

Middle Eastern (MID) AF: 0.294 AC: 1654 AN: 5620

European-Non Finnish (NFE) AF: 0.310 AC: 338404 AN: 1091828

Other (OTH) AF: 0.283 AC: 16643 AN: 58812

GnomAD4 genome AF: 0.256 AC: 39008 AN: 152128 Hom.: 5645 Cov.: 31 AF XY: 0.260 AC XY: 19337 AN XY: 74356

African (AFR) AF: 0.123 AC: 5103 AN: 41534

American (AMR) AF: 0.229 AC: 3499 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1043 AN: 3468

East Asian (EAS) AF: 0.318 AC: 1632 AN: 5140

South Asian (SAS) AF: 0.277 AC: 1334 AN: 4822

European-Finnish (FIN) AF: 0.392 AC: 4148 AN: 10586

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21354 AN: 67966

Other (OTH) AF: 0.250 AC: 530 AN: 2116

Alfa AF: 0.265 Hom.: 3088

Bravo AF: 0.238

Asia WGS AF: 0.224 AC: 779 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Uncertain	23
DANN	Benign	0.82
PhyloP100		1.3
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.88		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2271959; hg19: chr17-41622740; COSMIC: COSV60043759; COSMIC: COSV60043759;