1-27370346-G-T

Variant names:

• chr1-27370346-G-T
• rs4494157
• NM_003665.4:c.658+250C>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.658+250C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 484,418 control chromosomes in the GnomAD database, including 19,404 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.25 (5311 hom., cov: 32)
  • Exomes 𝑓: 0.28 (14093 hom.)
• Consequence: FCN3 NM_003665.4 intron
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: -0.403
• Publications: 12 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCN3	NM_003665.4	c.658+250C>A		intron_variant	Intron 7 of 7	ENST00000270879.9	NP_003656.2
FCN3	NM_173452.3	c.625+250C>A		intron_variant	Intron 6 of 6		NP_775628.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCN3	ENST00000270879.9	c.658+250C>A		intron_variant	Intron 7 of 7	1	NM_003665.4	ENSP00000270879.4

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37467 AN: 151972 Hom.: 5310 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.252

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.281

GnomAD4 exome AF: 0.277 AC: 91900 AN: 332328 Hom.: 14093 AF XY: 0.272 AC XY: 47662 AN XY: 175072

African (AFR) AF: 0.114 AC: 1159 AN: 10160

American (AMR) AF: 0.221 AC: 2592 AN: 11730

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 4165 AN: 10430

East Asian (EAS) AF: 0.113 AC: 2618 AN: 23130

South Asian (SAS) AF: 0.165 AC: 5596 AN: 33836

European-Finnish (FIN) AF: 0.249 AC: 5208 AN: 20892

Middle Eastern (MID) AF: 0.325 AC: 477 AN: 1466

European-Non Finnish (NFE) AF: 0.321 AC: 64691 AN: 201356

Other (OTH) AF: 0.279 AC: 5394 AN: 19328

GnomAD4 genome AF: 0.246 AC: 37472 AN: 152090 Hom.: 5311 Cov.: 32 AF XY: 0.242 AC XY: 18022 AN XY: 74344

African (AFR) AF: 0.121 AC: 5016 AN: 41492

American (AMR) AF: 0.243 AC: 3710 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1448 AN: 3470

East Asian (EAS) AF: 0.119 AC: 617 AN: 5178

South Asian (SAS) AF: 0.167 AC: 804 AN: 4826

European-Finnish (FIN) AF: 0.252 AC: 2664 AN: 10564

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.327 AC: 22196 AN: 67964

Other (OTH) AF: 0.279 AC: 589 AN: 2112

Alfa AF: 0.284 Hom.: 1089

Bravo AF: 0.244

Asia WGS AF: 0.135 AC: 469 AN: 3478

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Rheumatic heart disease Other:1

Jan 09, 2019

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

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: case-control

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.66
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4494157; hg19: chr1-27696837;