1-27370715-C-G

Variant names:

• chr1-27370715-C-G
• NM_003665.4:c.539G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003665.4(FCN3):​c.539G>C​(p.Arg180Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R180Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FCN3 NM_003665.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.183

Genes affected

FCN3 (HGNC:3625): (ficolin 3) Ficolins are a group of proteins which consist of a collagen-like domain and a fibrinogen-like domain. In human serum, there are two types of ficolins, both of which have lectin activity. The protein encoded by this gene is a thermolabile beta-2-macroglycoprotein found in all human serum and is a member of the ficolin/opsonin p35 lectin family. The protein, which was initially identified based on its reactivity with sera from patients with systemic lupus erythematosus, has been shown to have a calcium-independent lectin activity. The protein can activate the complement pathway in association with MASPs and sMAP, thereby aiding in host defense through the activation of the lectin pathway. Alternative splicing occurs at this locus and two variants, each encoding a distinct isoform, have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCN3	NM_003665.4	c.539G>C	p.Arg180Pro	missense_variant	Exon 7 of 8	ENST00000270879.9	NP_003656.2
FCN3	NM_173452.3	c.506G>C	p.Arg169Pro	missense_variant	Exon 6 of 7		NP_775628.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCN3	ENST00000270879.9	c.539G>C	p.Arg180Pro	missense_variant	Exon 7 of 8	1	NM_003665.4	ENSP00000270879.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.079	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	4.5	H;.
PrimateAI	Benign	0.21	T
PROVEAN	Pathogenic	-6.3	D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;.
Vest4		0.66
MutPred		0.74		Loss of sheet (P = 0.0817);.;
MVP		0.74
MPC		0.21
ClinPred		1.0	D
GERP RS		-4.3
Varity_R		0.77
gMVP		0.90

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: chr1-27697206;