rs1573643

Positions:

• chr15-90877743-T-C
• chr15-90877743-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002569.4(FURIN):​c.667+128T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 694,376 control chromosomes in the GnomAD database, including 36,577 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (8595 hom., cov: 33)
  • Exomes 𝑓: 0.31 (27982 hom.)
• Consequence: FURIN NM_002569.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.382

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FURIN	NM_002569.4	c.667+128T>C		intron_variant		ENST00000268171.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FURIN	ENST00000268171.8	c.667+128T>C		intron_variant		1	NM_002569.4	P1

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49967 AN: 152026 Hom.: 8583 Cov.: 33

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.354

Gnomad EAS AF: 0.0936

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.331

GnomAD4 exome AF: 0.312 AC: 169238 AN: 542232 Hom.: 27982 AF XY: 0.312 AC XY: 87577 AN XY: 280730

Gnomad4 AFR exome AF: 0.398

Gnomad4 AMR exome AF: 0.199

Gnomad4 ASJ exome AF: 0.352

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.280

Gnomad4 FIN exome AF: 0.271

Gnomad4 NFE exome AF: 0.340

Gnomad4 OTH exome AF: 0.313

GnomAD4 genome AF: 0.329 AC: 50007 AN: 152144 Hom.: 8595 Cov.: 33 AF XY: 0.322 AC XY: 23965 AN XY: 74390

Gnomad4 AFR AF: 0.394

Gnomad4 AMR AF: 0.263

Gnomad4 ASJ AF: 0.354

Gnomad4 EAS AF: 0.0942

Gnomad4 SAS AF: 0.262

Gnomad4 FIN AF: 0.259

Gnomad4 NFE AF: 0.336

Gnomad4 OTH AF: 0.330

Alfa AF: 0.340 Hom.: 2118

Bravo AF: 0.330

Asia WGS AF: 0.209 AC: 728 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1573643; hg19: chr15-91420973;