15-90868426-C-T

Variant names:

• chr15-90868426-C-T
• rs4932178
• NM_002569.4:c.-445C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002569.4(FURIN):​c.-445C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 152,006 control chromosomes in the GnomAD database, including 7,712 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 0.31 (7712 hom., cov: 32)
• Consequence: FURIN NM_002569.4 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.690
• Publications: 37 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.352 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FURIN	NM_002569.4	c.-445C>T		upstream_gene_variant		ENST00000268171.8	NP_002560.1
FURIN	NM_001382622.1	c.-445C>T		upstream_gene_variant			NP_001369551.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FURIN	ENST00000268171.8	c.-445C>T		upstream_gene_variant		1	NM_002569.4	ENSP00000268171.2

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47642 AN: 151888 Hom.: 7706 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.313

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

GnomAD4 genome AF: 0.314 AC: 47658 AN: 152006 Hom.: 7712 Cov.: 32 AF XY: 0.308 AC XY: 22922 AN XY: 74310

African (AFR) AF: 0.287 AC: 11891 AN: 41436

American (AMR) AF: 0.256 AC: 3910 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1479 AN: 3472

East Asian (EAS) AF: 0.164 AC: 848 AN: 5166

South Asian (SAS) AF: 0.279 AC: 1342 AN: 4808

European-Finnish (FIN) AF: 0.277 AC: 2927 AN: 10570

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.356 AC: 24199 AN: 67960

Other (OTH) AF: 0.314 AC: 662 AN: 2106

Alfa AF: 0.345 Hom.: 31560

Bravo AF: 0.309

Asia WGS AF: 0.247 AC: 858 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.1
DANN	Benign	0.68
PhyloP100		0.69
PromoterAI		0.024	Neutral

Splicing

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

Other links and lift over

dbSNP: rs4932178; hg19: chr15-91411656;