chr1-27370715-C-G

Variant names:

• chr1-27370715-C-G
• rs745814286
• NM_003665.4:c.539G>C

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

FCN3 Gene-Disease associations (from GenCC):

• immunodeficiency due to ficolin3 deficiency

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003665.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCN3	NM_003665.4	MANE Select	c.539G>C	p.Arg180Pro	missense	Exon 7 of 8	NP_003656.2
	FCN3	NM_173452.3		c.506G>C	p.Arg169Pro	missense	Exon 6 of 7	NP_775628.1	O75636-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCN3	ENST00000270879.9	TSL:1 MANE Select	c.539G>C	p.Arg180Pro	missense	Exon 7 of 8	ENSP00000270879.4	O75636-1
	FCN3	ENST00000354982.2	TSL:1	c.506G>C	p.Arg169Pro	missense	Exon 6 of 7	ENSP00000347077.2	O75636-2
	FCN3	ENST00000859507.1		c.770G>C	p.Arg257Pro	missense	Exon 8 of 9	ENSP00000529566.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	4.5	H
PhyloP100		-0.18
PrimateAI	Benign	0.21	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0090	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
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs745814286; hg19: chr1-27697206;