Genetic Variant FCN1:p.Arg93Gln (chr9-134914414-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002003.5(FCN1):c.278G>A(p.Arg93Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 1,613,976 control chromosomes in the GnomAD database, including 317 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.026 ( 155 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 162 hom. )

Consequence

FCN1
NM_002003.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.10

Publications

8 publications found

Variant links:

Genes affected

FCN1 (HGNC:3623): (ficolin 1) The ficolin family of proteins are characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. The collagen-like and the fibrinogen-like domains are also found separately in other proteins such as complement protein C1q, C-type lectins known as collectins, and tenascins. However, all these proteins recognize different targets, and are functionally distinct. Ficolin 1 encoded by FCN1 is predominantly expressed in the peripheral blood leukocytes, and has been postulated to function as a plasma protein with elastin-binding activity. [provided by RefSeq, Jul 2008]

FCN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019905865).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCN1	NM_002003.5 link	c.278G>A	p.Arg93Gln	missense_variant	Exon 4 of 9	ENST00000371806.4	NP_001994.2	O00602

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCN1	ENST00000371806.4 link	c.278G>A	p.Arg93Gln	missense_variant	Exon 4 of 9	1	NM_002003.5	ENSP00000360871.3		O00602

Frequencies

GnomAD3 genomes

AF:

0.0256

AC:

3897

AN:

152184

Hom.:

156

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0882

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0112

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.0186

GnomAD2 exomes

AF:

0.00681

AC:

1711

AN:

251394

AF XY:

0.00483

show subpopulations

Gnomad AFR exome

AF:

0.0903

Gnomad AMR exome

AF:

0.00555

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000761

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000202

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00261

AC:

3817

AN:

1461674

Hom.:

162

Cov.:

AF XY:

0.00218

AC XY:

1588

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.0881

AC:

2947

AN:

33458

American (AMR)

AF:

0.00601

AC:

269

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00365

AC:

145

AN:

39700

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000809

AC:

AN:

1111832

Other (OTH)

AF:

0.00576

AC:

348

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

177

353

530

706

883

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<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:

0.0256

AC:

3899

AN:

152302

Hom.:

155

Cov.:

AF XY:

0.0242

AC XY:

1804

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0880

AC:

3655

AN:

41526

American (AMR)

AF:

0.0112

AC:

172

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00174

AC:

AN:

5174

South Asian (SAS)

AF:

0.000621

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68038

Other (OTH)

AF:

0.0184

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

183

366

550

733

916

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:

0.0102

Hom.:

120

Bravo

AF:

0.0300

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0885

AC:

390

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00834

AC:

1012

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.20

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.19

.;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0027

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.3

.;L

PhyloP100

-3.1

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.15

.;N

REVEL

Benign

0.17

Sift

Benign

0.65

.;T

Sift4G

Benign

0.091

T;T

Polyphen

0.017

.;B

Vest4

0.13

MVP

0.65

MPC

0.14

ClinPred

0.00087

GERP RS

-4.0

Varity_R

0.025

gMVP

0.30

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over