NM_002569.4:c.667+95C>G

Variant names:

• chr15-90877710-C-G
• rs2071410
• NM_002569.4:c.667+95C>G

Variant summary

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

The NM_002569.4(FURIN):​c.667+95C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 835,496 control chromosomes in the GnomAD database, including 37,847 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 0.26 (5519 hom., cov: 33)
  • Exomes 𝑓: 0.30 (32328 hom.)
• Consequence: FURIN NM_002569.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.536
• Publications: 34 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FURIN	NM_002569.4	c.667+95C>G		intron_variant	Intron 7 of 15	ENST00000268171.8	NP_002560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FURIN	ENST00000268171.8	c.667+95C>G		intron_variant	Intron 7 of 15	1	NM_002569.4	ENSP00000268171.2

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39342 AN: 152094 Hom.: 5518 Cov.: 33

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.0695

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.252

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.266

GnomAD4 exome AF: 0.298 AC: 203401 AN: 683284 Hom.: 32328 AF XY: 0.297 AC XY: 103742 AN XY: 348824

African (AFR) AF: 0.187 AC: 3226 AN: 17234

American (AMR) AF: 0.172 AC: 4188 AN: 24404

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 5682 AN: 16308

East Asian (EAS) AF: 0.0837 AC: 2636 AN: 31490

South Asian (SAS) AF: 0.245 AC: 13062 AN: 53302

European-Finnish (FIN) AF: 0.264 AC: 10445 AN: 39530

Middle Eastern (MID) AF: 0.319 AC: 1274 AN: 4000

European-Non Finnish (NFE) AF: 0.331 AC: 153335 AN: 463348

Other (OTH) AF: 0.284 AC: 9553 AN: 33668

GnomAD4 genome AF: 0.259 AC: 39351 AN: 152212 Hom.: 5519 Cov.: 33 AF XY: 0.254 AC XY: 18921 AN XY: 74404

African (AFR) AF: 0.180 AC: 7458 AN: 41538

American (AMR) AF: 0.231 AC: 3533 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1211 AN: 3470

East Asian (EAS) AF: 0.0701 AC: 363 AN: 5182

South Asian (SAS) AF: 0.226 AC: 1089 AN: 4826

European-Finnish (FIN) AF: 0.252 AC: 2668 AN: 10606

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.325 AC: 22125 AN: 67980

Other (OTH) AF: 0.266 AC: 562 AN: 2110

Alfa AF: 0.178 Hom.: 413

Bravo AF: 0.252

Asia WGS AF: 0.171 AC: 596 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.4
DANN	Benign	0.53
PhyloP100		-0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2071410; hg19: chr15-91420940; COSMIC: COSV51578518; COSMIC: COSV51578518;