Genetic Variant FCN1:c.-144C>A (chr9-134918015-G-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.-144C>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 587,078 control chromosomes in the GnomAD database, including 23,215 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.25 ( 5430 hom., cov: 32)

Exomes 𝑓: 0.27 ( 17785 hom. )

Consequence

FCN1
NM_002003.5 upstream_gene

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0310

Publications

29 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 (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCN1	NM_002003.5 link	c.-144C>A		upstream_gene_variant		ENST00000371806.4	NP_001994.2	O00602

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCN1	ENST00000371806.4 link	c.-144C>A		upstream_gene_variant		1	NM_002003.5	ENSP00000360871.3		O00602

Frequencies

GnomAD3 genomes

AF:

0.250

AC:

37977

AN:

151954

Hom.:

5431

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.503

Gnomad AMR

AF:

0.215

Gnomad ASJ

AF:

0.249

Gnomad EAS

AF:

0.00809

Gnomad SAS

AF:

0.181

Gnomad FIN

AF:

0.344

Gnomad MID

AF:

0.263

Gnomad NFE

AF:

0.331

Gnomad OTH

AF:

0.252

GnomAD4 exome

AF:

0.269

AC:

117109

AN:

435006

Hom.:

17785

AF XY:

0.266

AC XY:

61001

AN XY:

229092

show subpopulations

African (AFR)

AF:

0.136

AC:

1666

AN:

12284

American (AMR)

AF:

0.171

AC:

3418

AN:

19964

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

3163

AN:

13336

East Asian (EAS)

AF:

0.00246

AC:

AN:

29708

South Asian (SAS)

AF:

0.199

AC:

8885

AN:

44728

European-Finnish (FIN)

AF:

0.313

AC:

8965

AN:

28668

Middle Eastern (MID)

AF:

0.283

AC:

592

AN:

2094

European-Non Finnish (NFE)

AF:

0.323

AC:

83734

AN:

259226

Other (OTH)

AF:

0.265

AC:

6613

AN:

24998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

3525

7050

10575

14100

17625

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.250

AC:

37968

AN:

152072

Hom.:

5430

Cov.:

AF XY:

0.247

AC XY:

18327

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.137

AC:

5700

AN:

41504

American (AMR)

AF:

0.215

AC:

3284

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.249

AC:

862

AN:

3466

East Asian (EAS)

AF:

0.00792

AC:

AN:

5180

South Asian (SAS)

AF:

0.181

AC:

870

AN:

4816

European-Finnish (FIN)

AF:

0.344

AC:

3637

AN:

10566

Middle Eastern (MID)

AF:

0.272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.331

AC:

22513

AN:

67950

Other (OTH)

AF:

0.248

AC:

523

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1418

2836

4253

5671

7089

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.280

Hom.:

3598

Bravo

AF:

0.235

Asia WGS

AF:

0.100

AC:

347

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 22, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22673311, 23209787) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.7

(source)

DANN

Benign

0.37

PhyloP100

-0.031

PromoterAI

0.23

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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9-134918015-G-T

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