NM_003665.4:c.797G>C

Variant names:

• chr1-27369339-C-G
• rs746674895
• NM_003665.4:c.797G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003665.4(FCN3):​c.797G>C​(p.Arg266Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R266H) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: FCN3 NM_003665.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.32
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22156149).

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.797G>C	p.Arg266Pro	missense	Exon 8 of 8	NP_003656.2
	FCN3	NM_173452.3		c.764G>C	p.Arg255Pro	missense	Exon 7 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.797G>C	p.Arg266Pro	missense	Exon 8 of 8	ENSP00000270879.4	O75636-1
	FCN3	ENST00000354982.2	TSL:1	c.764G>C	p.Arg255Pro	missense	Exon 7 of 7	ENSP00000347077.2	O75636-2
	FCN3	ENST00000859507.1		c.1028G>C	p.Arg343Pro	missense	Exon 9 of 9	ENSP00000529566.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	1.0
DANN	Benign	0.89
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.33	N
PhyloP100		-4.3
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.27
Sift	Benign	0.21	T
Sift4G	Benign	0.30	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.66		Loss of MoRF binding (P = 0.011)
MVP		0.66
MPC		0.19
ClinPred		0.056	T
GERP RS		-3.6
Varity_R		0.86
gMVP		0.65
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs746674895; hg19: chr1-27695830;