chr1-27373179-AG-A

Position:

• chr1-27373179-AG-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The ENST00000270879.9(FCN3):​c.349del​(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 ENST00000270879.9 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:2 U:2
• Conservation: PhyloP100: -0.0450

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 Likely_benign. Variant got -5 ACMG points.

• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCN3	NM_003665.4	c.349del	p.Leu117SerfsTer65	frameshift_variant	5/8	ENST00000270879.9	NP_003656.2
FCN3	NM_173452.3	c.316del	p.Leu106SerfsTer65	frameshift_variant	4/7		NP_775628.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FCN3	ENST00000270879.9	c.349del	p.Leu117SerfsTer65	frameshift_variant	5/8	1	NM_003665.4	ENSP00000270879	P2

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

GnomAD3 exomes AF: 0.0161 AC: 4052 AN: 251186 Hom.: 53 AF XY: 0.0169 AC XY: 2299 AN XY: 135826

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 SAS exome AF: 0.0283

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

Gnomad4 AFR exome AF: 0.0228

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.0277

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0305

Gnomad4 FIN exome AF: 0.00843

Gnomad4 NFE exome AF: 0.0149

Gnomad4 OTH exome AF: 0.0184

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

Gnomad4 AFR AF: 0.0260

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.0262

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0292

Gnomad4 FIN AF: 0.00707

Gnomad4 NFE AF: 0.0171

Gnomad4 OTH AF: 0.0222

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

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency due to ficolin3 deficiency Pathogenic:2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_003665.2:c.349delC in the FCN3 gene has an allele frequency of 0.028 in South Asian subpopulation in the gnomAD database. The c.349delC variant has been identified in the homozygous state in 3 individuals with Immunodeficiency (PMID: 19535802; 20971976; 22226667). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PVS1; PM3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 19, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 18, 2009	- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs532781899; hg19: chr1-27699670;