1-27373179-AGG-AG

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PVS1BS1_SupportingBS2

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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:3

Conservation

PhyloP100: -0.0450

Publications

46 publications found

Variant links:

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

FCN3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCN3	NM_003665.4 link	c.349delC	p.Leu117SerfsTer65	frameshift_variant	Exon 5 of 8	ENST00000270879.9	NP_003656.2	O75636-1Q6UY50
FCN3	NM_173452.3 link	c.316delC	p.Leu106SerfsTer65	frameshift_variant	Exon 4 of 7		NP_775628.1	O75636-2Q6UXM4Q6UY50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCN3	ENST00000270879.9 link	c.349delC	p.Leu117SerfsTer65	frameshift_variant	Exon 5 of 8	1	NM_003665.4	ENSP00000270879.4		O75636-1

Frequencies

GnomAD3 genomes

AF:

0.0184

AC:

2805

AN:

152110

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0164

AC XY:

11942

AN XY:

727192

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1200

2401

3601

4802

6002

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

626

1252

1878

2504

3130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0184

AC:

2806

AN:

152228

Hom.:

Cov.:

AF XY:

0.0181

AC XY:

1350

AN XY:

74432

show subpopulations

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:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5164

South Asian (SAS)

AF:

0.0292

AC:

141

AN:

4828

European-Finnish (FIN)

AF:

0.00707

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0171

AC:

1166

AN:

68006

Other (OTH)

AF:

0.0222

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

133

266

398

531

664

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00584

Hom.:

Bravo

AF:

0.0192

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.0202

EpiControl

AF:

0.0214

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency due to ficolin3 deficiency

Pathogenic:2Uncertain:3

Feb 27, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jun 18, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.045

Mutation Taster

=190/10

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over