1-27370933-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003665.4(FCN3):c.433C>T(p.Arg145Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: FCN3 NM_003665.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.276

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.122757256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FCN3	NM_003665.4	c.433C>T	p.Arg145Cys	missense_variant	6/8	ENST00000270879.9
FCN3	NM_173452.3	c.400C>T	p.Arg134Cys	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FCN3	ENST00000270879.9	c.433C>T	p.Arg145Cys	missense_variant	6/8	1	NM_003665.4	P2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.0000399 AC: 10 AN: 250728 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135630

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461474 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 727016

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74412

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.0000494 Hom.: 0

Bravo AF: 0.000162

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000577 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

FCN3-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2023

The FCN3 c.433C>T variant is predicted to result in the amino acid substitution p.Arg145Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.036% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-27697424-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.034	N
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Pathogenic	4.5	H;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Benign	0.13
Sift	Benign	0.050	D;T
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.40
MVP		0.53
MPC		0.19
ClinPred		0.25	T
GERP RS		-0.84
Varity_R		0.49
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs373443059; hg19: chr1-27697424;