1-27373179-AGG-AG

Variant names:

• chr1-27373179-AG-A
• rs532781899
• NM_003665.4:c.349delC

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PVS1 BS1_Supporting BS2

The NM_003665.4(FCN3):​c.349delC​(p.Leu117SerfsTer65) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,613,992 control chromosomes in the GnomAD database, including 299 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.018 (34 hom., cov: 31)
  • Exomes 𝑓: 0.016 (265 hom.)
• Consequence: FCN3 NM_003665.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:2 U:4
• Conservation: PhyloP100: -0.0450
• Publications: 46 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 3 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0184 (2806/152228) while in subpopulation SAS AF = 0.0292 (141/4828). AF 95% confidence interval is 0.0253. There are 34 homozygotes in GnomAd4. There are 1350 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

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.349delC	p.Leu117SerfsTer65	frameshift	Exon 5 of 8	NP_003656.2
	FCN3	NM_173452.3		c.316delC	p.Leu106SerfsTer65	frameshift	Exon 4 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.349delC	p.Leu117SerfsTer65	frameshift	Exon 5 of 8	ENSP00000270879.4	O75636-1
	FCN3	ENST00000354982.2	TSL:1	c.316delC	p.Leu106SerfsTer65	frameshift	Exon 4 of 7	ENSP00000347077.2	O75636-2
	FCN3	ENST00000859507.1		c.349delC	p.Leu117SerfsTer15	frameshift	Exon 5 of 9	ENSP00000529566.1

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2805 AN: 152110 Hom.: 34 Cov.: 31

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.0262

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.00707

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.0161 AC: 4052 AN: 251186 AF XY: 0.0169

Gnomad AFR exome AF: 0.0248

Gnomad AMR exome AF: 0.00984

Gnomad ASJ exome AF: 0.0258

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00841

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0207

GnomAD4 exome AF: 0.0157 AC: 22973 AN: 1461764 Hom.: 265 Cov.: 32 AF XY: 0.0164 AC XY: 11942 AN XY: 727192

African (AFR) AF: 0.0228 AC: 763 AN: 33480

American (AMR) AF: 0.0103 AC: 460 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 725 AN: 26130

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

South Asian (SAS) AF: 0.0305 AC: 2631 AN: 86258

European-Finnish (FIN) AF: 0.00843 AC: 450 AN: 53358

Middle Eastern (MID) AF: 0.0427 AC: 246 AN: 5766

European-Non Finnish (NFE) AF: 0.0149 AC: 16585 AN: 1111966

Other (OTH) AF: 0.0184 AC: 1113 AN: 60390

GnomAD4 genome AF: 0.0184 AC: 2806 AN: 152228 Hom.: 34 Cov.: 31 AF XY: 0.0181 AC XY: 1350 AN XY: 74432

African (AFR) AF: 0.0260 AC: 1078 AN: 41532

American (AMR) AF: 0.0125 AC: 191 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 91 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5164

South Asian (SAS) AF: 0.0292 AC: 141 AN: 4828

European-Finnish (FIN) AF: 0.00707 AC: 75 AN: 10610

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0171 AC: 1166 AN: 68006

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.00584 Hom.: 2

Bravo AF: 0.0192

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.0202

EpiControl AF: 0.0214

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	4	-	Immunodeficiency due to ficolin3 deficiency (6)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.045
Mutation Taster		=190/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs532781899; hg19: chr1-27699670; COSMIC: COSV54640803; COSMIC: COSV54640803;