1-27369386-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003665.4(FCN3):c.750C>T(p.His250=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,614,204 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (22 hom.)
• Consequence: FCN3 NM_003665.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -7.17

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-27369386-G-A is Benign according to our data. Variant chr1-27369386-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 710189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-27369386-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-7.17 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FCN3	NM_003665.4	c.750C>T	p.His250=	synonymous_variant	8/8	ENST00000270879.9
FCN3	NM_173452.3	c.717C>T	p.His239=	synonymous_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FCN3	ENST00000270879.9	c.750C>T	p.His250=	synonymous_variant	8/8	1	NM_003665.4	P2
FCN3	ENST00000354982.2	c.717C>T	p.His239=	synonymous_variant	7/7	1		A2
FCN3	ENST00000699962.1	n.749C>T		non_coding_transcript_exon_variant	7/7

Frequencies

GnomAD3 genomes AF: 0.00252 AC: 384 AN: 152230 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00403

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00322 AC: 810 AN: 251490 Hom.: 2 AF XY: 0.00336 AC XY: 457 AN XY: 135920

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00685

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00389

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00447

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00389 AC: 5691 AN: 1461856 Hom.: 22 Cov.: 32 AF XY: 0.00394 AC XY: 2864 AN XY: 727222

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.00869

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00373

Gnomad4 FIN exome AF: 0.000468

Gnomad4 NFE exome AF: 0.00419

Gnomad4 OTH exome AF: 0.00460

GnomAD4 genome AF: 0.00251 AC: 383 AN: 152348 Hom.: 1 Cov.: 33 AF XY: 0.00208 AC XY: 155 AN XY: 74516

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00403

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00437 Hom.: 4

Bravo AF: 0.00262

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00379

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	FCN3: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jun 14, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Immunodeficiency due to ficolin3 deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.23
Dann	Benign	0.90

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

Other links and lift over

dbSNP: rs28385652; hg19: chr1-27695877; COSMIC: COSV54641055; COSMIC: COSV54641055;