1-27370868-C-G

Position:

chr1-27370868-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_003665.4(FCN3):c.498G>C(p.Glu166Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,614,128 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0012 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 31 hom. )

Consequence

FCN3
NM_003665.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:3

Conservation

PhyloP100: -0.140

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 links:

FCN3 (HGNC:):

FCN3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00455755).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00116 (177/152274) while in subpopulation EAS AF= 0.0301 (156/5178). AF 95% confidence interval is 0.0263. There are 4 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCN3	NM_003665.4 linkuse as main transcript	c.498G>C	p.Glu166Asp	missense_variant	6/8	ENST00000270879.9	NP_003656.2	O75636-1Q6UY50
FCN3	NM_173452.3 linkuse as main transcript	c.465G>C	p.Glu155Asp	missense_variant	5/7		NP_775628.1	O75636-2Q6UXM4Q6UY50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FCN3	ENST00000270879.9 linkuse as main transcript	c.498G>C	p.Glu166Asp	missense_variant	6/8	1	NM_003665.4	ENSP00000270879.4		O75636-1

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

179

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0304

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00257

AC:

646

AN:

251398

Hom.:

AF XY:

0.00248

AC XY:

337

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0329

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00112

AC:

1633

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

794

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0359

Gnomad4 SAS exome

AF:

0.000626

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00222

GnomAD4 genome

AF:

0.00116

AC:

177

AN:

152274

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0301

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00139

Hom.:

Bravo

AF:

0.00151

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00259

AC:

314

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

- -

Immunodeficiency due to ficolin3 deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 18, 2022

- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.028

T;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.85

T;T

MetaRNN

Benign

0.0046

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.10

N;.

PrimateAI

Benign

0.36

PROVEAN

Benign

1.6

N;N

REVEL

Benign

0.13

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.022

B;.

Vest4

0.24

MutPred

0.50

Loss of helix (P = 0.1299);.;

MVP

0.43

MPC

0.52

ClinPred

0.025

GERP RS

4.0

Varity_R

0.27

gMVP

0.57

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over