rs141853578

Positions:

• chr4-109764664-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000204.5(CFI):​c.355G>A​(p.Gly119Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000763 in 1,613,848 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (3 hom.)
• Consequence: CFI NM_000204.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4 B:1 O:2
• Conservation: PhyloP100: 1.71

Genes affected

CFI (HGNC:5394): (complement factor I) This gene encodes a serine proteinase that is essential for regulating the complement cascade. The encoded preproprotein is cleaved to produce both heavy and light chains, which are linked by disulfide bonds to form a heterodimeric glycoprotein. This heterodimer can cleave and inactivate the complement components C4b and C3b, and it prevents the assembly of the C3 and C5 convertase enzymes. Defects in this gene cause complement factor I deficiency, an autosomal recessive disease associated with a susceptibility to pyogenic infections. Mutations in this gene have been associated with a predisposition to atypical hemolytic uremic syndrome, a disease characterized by acute renal failure, microangiopathic hemolytic anemia and thrombocytopenia. Primary glomerulonephritis with immune deposits and age-related macular degeneration are other conditions associated with mutations of this gene. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000802 (1173/1461706) while in subpopulation NFE AF= 0.00102 (1136/1111942). AF 95% confidence interval is 0.000972. There are 3 homozygotes in gnomad4_exome. There are 564 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFI	NM_000204.5	c.355G>A	p.Gly119Arg	missense_variant	3/13	ENST00000394634.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFI	ENST00000394634.7	c.355G>A	p.Gly119Arg	missense_variant	3/13	1	NM_000204.5	P2

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000422 AC: 106 AN: 251328 Hom.: 0 AF XY: 0.000456 AC XY: 62 AN XY: 135832

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000927

Gnomad NFE exome AF: 0.000853

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000802 AC: 1173 AN: 1461706 Hom.: 3 Cov.: 31 AF XY: 0.000776 AC XY: 564 AN XY: 727170

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74332

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00111 Hom.: 1

Bravo AF: 0.000427

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000527 AC: 64

EpiCase AF: 0.000763

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4 Benign:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2022	Published functional studies demonstrate reduced expression and activity (van de Ven et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20513133, 23685748, 26767664, 28637922, 28282489, 27939104, 27380463, 29398083, 29410599, 31528764, 31614353, 32510551, 32832254, 25352734, 24036952, 26691988, 29087762, 27918759, 29700787, 29888403, 29392637, 20203157, 32516404, 32195675, 33610747, 34153144, 34945728, 34169201) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 22, 2020	PS3, PS4, PP3 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

Atypical hemolytic-uremic syndrome with I factor anomaly Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Nov 06, 2020	Evidence in support of status as susceptibility allele: - Variant is present in gnomAD (v2) <0.001 for a dominant condition (120 heterozygotes, 0 homozygotes). - This variant has been reported as a susceptibility factor for aHUS and has been reported in patients with aHUS (PMIDs: 27177491, 20513133 and ClinVar). Additional information: - Loss of function in this gene is associated with susceptibility to atypical haemolytic uraemic syndrome (aHUS) 3 (MIM#612923). - This gene is associated with autosomal recessive complement factor I deficiency (MIM#610984). Monoallelic variants in this gene are associated with susceptibility to aHUS 3 (MIM#612923). - Variant is predicted to result in a missense amino acid change from glycine to arginine. - This variant is heterozygous. - Missense variant with conflicting in silico predictions and uninformative conservation. - Variant is located in the annotated CD5 domain (PMID: 20513133). - This variant has been shown to be maternally inherited (by trio analysis). -
risk factor, no assertion criteria provided	literature only	OMIM	Jul 01, 2013	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2024	Variant summary: CFI c.355G>A (p.Gly119Arg) results in a non-conservative amino acid change located in the SRCR domain (IPR001190) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00076 in 1613848 control chromosomes, predominantly at a frequency of 0.001 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. This frequency is approximately equal to the maximum estimated frequency for a pathogenic variant in CFI causing Complement Factor I Deficiency ( 0.001 vs 0.0011) and is much higher than estimated for a pathogenic variant causing an autosomal dominant condition such as Atypical Hemolytic Uremic Syndrome, suggesting this variant may be benign. c.355G>A has been reported in the literature in the heterozygous state in multiple individuals affected with Atypical Hemolytic Uremic Syndrome and Age-related Macular Degeneration, without strong evidence for pathogenicity (i.e. segregation data) and has also been reported in healthy controls (e.g. Maga_2010, van de Ven_2013, de Jong_2020, Zhang_2022). It has been reported in at least two presumably compound heterozygous individuals (phase unspecified) with Atypical Hemolytic Uremic Syndrome/C3 glomerulopathy who were not described as having clinical features of Complement Factor I Deficiency (e.g. Maga_2010, Zhang_2022) and to our knowledge, this variant has not been reported in individuals with this condition. These reports do not provide unequivocal conclusions about association of the variant with disease. At least two publications report experimental evidence evaluating an impact on protein function (van de Ven_2013, de Jong_2020). The variant results in decreased expression and secretion in vitro, but has a higher efficiency versus the WT protein. Heterozygous carriers of the variant have been found to have reduced FI plasma levels, at approximately 55-60% of normal, however the clinical significance of this with respect to disease manifestation is unclear (de Jong_2020). The following publications have been ascertained in the context of this evaluation (PMID: 20513133, 35619721, 32510551, 23685748). ClinVar contains an entry for this variant (Variation ID: 66014). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Factor I deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 28, 2021

- -

Atypical hemolytic-uremic syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Feb 21, 2019

This individual is heterozygous for the c.355G>A variant in the CFI gene, which results in the amino acid substitution of glycine to arginine at residue 119, p.(Gly119Arg). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with an allele frequency of 0.09% (110 out of 129,124 alleles) in the European non-Finnish population. This variant has been reported in the Database of complement gene variants (https://www.complement-db.org/home.php) as a VOUS in 16 individuals with aHUS with and without a second variant in CFI or another complement gene. p.Gly119Arg has been reported in ClinVar as a VOUS (variation ID 66014). p.Gly119Arg has also been reported to confer high risk of developing age-related macular degeneration (ARMD) (van de Ven et al 2013 Nat Genet 45:813-817 and Fritsche et al 2016 Nat Genet. 48:134-143). In vitro functional studies were performed by van de Ven et al 2013 and showed that the Gly119Arg mutant protein resulted in lower levels of expression and secretion compared to wild-type protein. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines (Evidence used: PS3). -

Macular degeneration, age-related, 13, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.079
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.81	T;T;T;T;T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.091	T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.40	T
Polyphen		0.98, 0.97, 0.94	.;D;D;.;P;.
Vest4		0.40, 0.38, 0.55, 0.38, 0.19
MutPred		0.93		Gain of solvent accessibility (P = 0.1319);Gain of solvent accessibility (P = 0.1319);Gain of solvent accessibility (P = 0.1319);Gain of solvent accessibility (P = 0.1319);Gain of solvent accessibility (P = 0.1319);Gain of solvent accessibility (P = 0.1319);
MVP		0.73
MPC		0.11
ClinPred		0.14	T
GERP RS		5.6
Varity_R		0.45
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.35		Position offset: 26

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

Publications

LitVar

Other links and lift over

dbSNP: rs141853578; hg19: chr4-110685820;