chr1-27372958-A-T

Variant names:

• chr1-27372958-A-T
• rs10794501
• NM_003665.4:c.393+178T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003665.4(FCN3):​c.393+178T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 151,848 control chromosomes in the GnomAD database, including 37,474 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: 𝑓 0.69 (37474 hom., cov: 29)
• Consequence: FCN3 NM_003665.4 intron
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.153
• Publications: 5 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003665.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCN3	NM_003665.4	MANE Select	c.393+178T>A		intron	N/A	NP_003656.2
	FCN3	NM_173452.3		c.360+178T>A		intron	N/A	NP_775628.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCN3	ENST00000270879.9	TSL:1 MANE Select	c.393+178T>A		intron	N/A	ENSP00000270879.4
	FCN3	ENST00000354982.2	TSL:1	c.360+178T>A		intron	N/A	ENSP00000347077.2
	FCN3	ENST00000699963.1		c.393+178T>A		intron	N/A	ENSP00000514719.1

Frequencies

GnomAD3 genomes AF: 0.695 AC: 105391 AN: 151730 Hom.: 37450 Cov.: 29

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.838

Gnomad AMR AF: 0.764

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.900

Gnomad SAS AF: 0.792

Gnomad FIN AF: 0.767

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.739

Gnomad OTH AF: 0.685

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.694 AC: 105458 AN: 151848 Hom.: 37474 Cov.: 29 AF XY: 0.701 AC XY: 52034 AN XY: 74228

African (AFR) AF: 0.540 AC: 22349 AN: 41376

American (AMR) AF: 0.765 AC: 11650 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 2292 AN: 3466

East Asian (EAS) AF: 0.900 AC: 4646 AN: 5164

South Asian (SAS) AF: 0.793 AC: 3817 AN: 4816

European-Finnish (FIN) AF: 0.767 AC: 8083 AN: 10544

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.739 AC: 50243 AN: 67942

Other (OTH) AF: 0.684 AC: 1438 AN: 2102

Alfa AF: 0.712 Hom.: 4593

Bravo AF: 0.685

Asia WGS AF: 0.836 AC: 2906 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Rheumatic heart disease Uncertain:1

Jan 09, 2019

Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: case-control

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.6
DANN	Benign	0.86
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs10794501; hg19: chr1-27699449;