rs17514846

Positions:

• chr15-90873320-C-A
• chr15-90873320-C-G
• chr15-90873320-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002569.4(FURIN):​c.-159-2262C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 151,950 control chromosomes in the GnomAD database, including 23,986 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.53 (23986 hom., cov: 31)
• Consequence: FURIN NM_002569.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.343

Genes affected

FURIN (HGNC:8568): (furin, paired basic amino acid cleaving enzyme) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. It encodes a type 1 membrane bound protease that is expressed in many tissues, including neuroendocrine, liver, gut, and brain. The encoded protein undergoes an initial autocatalytic processing event in the ER and then sorts to the trans-Golgi network through endosomes where a second autocatalytic event takes place and the catalytic activity is acquired. Like other members of this convertase family, the product of this gene specifically cleaves substrates at single or paired basic residues. Some of its substrates include proparathyroid hormone, transforming growth factor beta 1 precursor, proalbumin, pro-beta-secretase, membrane type-1 matrix metalloproteinase, beta subunit of pro-nerve growth factor and von Willebrand factor. It is thought to be one of the proteases responsible for the activation of HIV envelope glycoproteins gp160 and gp140, and may play a role in tumor progression. Unlike SARS-CoV and other coronaviruses, the spike protein of SARS-CoV-2 is thought to be uniquely cleaved by this protease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 15-90873320-C-A is Benign according to our data. Variant chr15-90873320-C-A is described in ClinVar as [Benign]. Clinvar id is 1265365.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FURIN	NM_002569.4	c.-159-2262C>A		intron_variant		ENST00000268171.8	NP_002560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FURIN	ENST00000268171.8	c.-159-2262C>A		intron_variant		1	NM_002569.4	ENSP00000268171	P1
FURIN	ENST00000610579.4	c.-160+1715C>A		intron_variant		5		ENSP00000484952	P1
FURIN	ENST00000618099.4	c.-160+222C>A		intron_variant		5		ENSP00000483552	P1
FURIN	ENST00000680053.1	c.-160+1094C>A		intron_variant				ENSP00000506143	P1

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80413 AN: 151832 Hom.: 23934 Cov.: 31

Gnomad AFR AF: 0.818

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.481

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.530 AC: 80519 AN: 151950 Hom.: 23986 Cov.: 31 AF XY: 0.519 AC XY: 38549 AN XY: 74264

Gnomad4 AFR AF: 0.818

Gnomad4 AMR AF: 0.354

Gnomad4 ASJ AF: 0.490

Gnomad4 EAS AF: 0.159

Gnomad4 SAS AF: 0.378

Gnomad4 FIN AF: 0.380

Gnomad4 NFE AF: 0.461

Gnomad4 OTH AF: 0.481

Alfa AF: 0.451 Hom.: 26096

Bravo AF: 0.539

Asia WGS AF: 0.339 AC: 1181 AN: 3478

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

GeneDx

Jan 10, 2019

This variant is associated with the following publications: (PMID: 23202125, 29976768) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.5
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs17514846; hg19: chr15-91416550;