rs6227

Variant names:

• chr15-90882002-C-T
• rs6227
• NM_002569.4:c.*124C>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.*124C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 709,594 control chromosomes in the GnomAD database, including 31,744 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 0.28 (6233 hom., cov: 33)
  • Exomes 𝑓: 0.29 (25511 hom.)
• Consequence: FURIN NM_002569.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53
• Publications: 47 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FURIN	NM_002569.4	c.*124C>T		3_prime_UTR_variant	Exon 16 of 16	ENST00000268171.8	NP_002560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FURIN	ENST00000268171.8	c.*124C>T		3_prime_UTR_variant	Exon 16 of 16	1	NM_002569.4	ENSP00000268171.2

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42576 AN: 151976 Hom.: 6223 Cov.: 33

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.0691

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.280

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.283

GnomAD4 exome AF: 0.290 AC: 161870 AN: 557500 Hom.: 25511 Cov.: 7 AF XY: 0.289 AC XY: 83974 AN XY: 290128

African (AFR) AF: 0.253 AC: 3542 AN: 14008

American (AMR) AF: 0.182 AC: 3733 AN: 20532

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 4962 AN: 14410

East Asian (EAS) AF: 0.0752 AC: 2332 AN: 31006

South Asian (SAS) AF: 0.237 AC: 11519 AN: 48518

European-Finnish (FIN) AF: 0.263 AC: 11364 AN: 43280

Middle Eastern (MID) AF: 0.307 AC: 692 AN: 2252

European-Non Finnish (NFE) AF: 0.326 AC: 115428 AN: 354502

Other (OTH) AF: 0.286 AC: 8298 AN: 28992

GnomAD4 genome AF: 0.280 AC: 42609 AN: 152094 Hom.: 6233 Cov.: 33 AF XY: 0.274 AC XY: 20406 AN XY: 74346

African (AFR) AF: 0.254 AC: 10517 AN: 41486

American (AMR) AF: 0.240 AC: 3663 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1207 AN: 3466

East Asian (EAS) AF: 0.0696 AC: 360 AN: 5172

South Asian (SAS) AF: 0.221 AC: 1067 AN: 4826

European-Finnish (FIN) AF: 0.251 AC: 2662 AN: 10590

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.327 AC: 22190 AN: 67952

Other (OTH) AF: 0.283 AC: 597 AN: 2108

Alfa AF: 0.317 Hom.: 5639

Bravo AF: 0.277

Asia WGS AF: 0.172 AC: 600 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6227; hg19: chr15-91425232; COSMIC: COSV51579524; COSMIC: COSV51579524;