15-90876535-A-C

Position:

• chr15-90876535-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002569.4(FURIN):​c.350A>C​(p.Lys117Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FURIN NM_002569.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.08

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3691159).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FURIN	NM_002569.4	c.350A>C	p.Lys117Thr	missense_variant	4/16	ENST00000268171.8	NP_002560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FURIN	ENST00000268171.8	c.350A>C	p.Lys117Thr	missense_variant	4/16	1	NM_002569.4	ENSP00000268171.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2021

The c.350A>C (p.K117T) alteration is located in exon 4 (coding exon 3) of the FURIN gene. This alteration results from a A to C substitution at nucleotide position 350, causing the lysine (K) at amino acid position 117 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D;D;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.075
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	.;D;.;D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.6	M;M;M;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.8	D;.;.;D
REVEL	Uncertain	0.36
Sift	Benign	0.39	T;.;.;T
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.042	B;B;B;.
Vest4		0.63
MutPred		0.41		Loss of methylation at K117 (P = 2e-04);Loss of methylation at K117 (P = 2e-04);Loss of methylation at K117 (P = 2e-04);.;
MVP		0.71
MPC		1.4
ClinPred		0.84	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-91419765; COSMIC: COSV99184613; COSMIC: COSV99184613;