9-134909977-A-G

Position:

• chr9-134909977-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_002003.5(FCN1):​c.802T>C​(p.Ser268Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,614,110 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (7 hom.)
• Consequence: FCN1 NM_002003.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.11

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity FCN1_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.020994157).
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCN1	NM_002003.5	c.802T>C	p.Ser268Pro	missense_variant	9/9	ENST00000371806.4	NP_001994.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FCN1	ENST00000371806.4	c.802T>C	p.Ser268Pro	missense_variant	9/9	1	NM_002003.5	ENSP00000360871	P1

Frequencies

GnomAD3 genomes AF: 0.000953 AC: 145 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00114 AC: 287 AN: 251494 Hom.: 1 AF XY: 0.00126 AC XY: 171 AN XY: 135920

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00278

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00152

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00192 AC: 2810 AN: 1461874 Hom.: 7 Cov.: 34 AF XY: 0.00193 AC XY: 1405 AN XY: 727236

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.000650

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00343

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00210

Gnomad4 OTH exome AF: 0.00195

GnomAD4 genome AF: 0.000959 AC: 146 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000927 AC XY: 69 AN XY: 74470

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00173

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00143 Hom.: 2

Bravo AF: 0.00110

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00101 AC: 123

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00130

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene associated with immunodeficiency. However, the variant has high frequency and there is only 1 paper which describes a correlation between presence of this variant and M-ficolin levels. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.098
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.026	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.63
Sift	Benign	0.061	T
Sift4G	Benign	0.092	T
Polyphen		0.85	P
Vest4		0.21
MVP		0.87
MPC		0.29
ClinPred		0.060	T
GERP RS		-1.8
Varity_R		0.69
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150625869; hg19: chr9-137801823;