15-90877743-T-G

Variant names:

• chr15-90877743-T-G
• rs1573643
• NM_002569.4:c.667+128T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002569.4(FURIN):​c.667+128T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FURIN NM_002569.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.382
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002569.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FURIN	NM_002569.4	MANE Select	c.667+128T>G		intron	N/A	NP_002560.1
	FURIN	NM_001289823.2		c.667+128T>G		intron	N/A	NP_001276752.1
	FURIN	NM_001289824.2		c.667+128T>G		intron	N/A	NP_001276753.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FURIN	ENST00000268171.8	TSL:1 MANE Select	c.667+128T>G		intron	N/A	ENSP00000268171.2
	FURIN	ENST00000610579.4	TSL:5	c.667+128T>G		intron	N/A	ENSP00000484952.1
	FURIN	ENST00000618099.4	TSL:5	c.667+128T>G		intron	N/A	ENSP00000483552.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 543038 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 281152

African (AFR) AF: 0.00 AC: 0 AN: 14268

American (AMR) AF: 0.00 AC: 0 AN: 20800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14650

East Asian (EAS) AF: 0.00 AC: 0 AN: 30694

South Asian (SAS) AF: 0.00 AC: 0 AN: 47532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3416

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 349446

Other (OTH) AF: 0.00 AC: 0 AN: 29048

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	14
DANN	Benign	0.55
PhyloP100		-0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.35		Position offset: 1

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

Other links and lift over

dbSNP: rs1573643; hg19: chr15-91420973;