chr4-109764664-C-T

Variant names:

• chr4-109764664-C-T
• rs141853578
• NM_000204.5:c.355G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 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:4 U:6 B:1 O:2
• Conservation: PhyloP100: 1.71
• Publications: 77 publications found

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]

CFI Gene-Disease associations (from GenCC):

• atypical hemolytic-uremic syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• atypical hemolytic-uremic syndrome with I factor anomaly

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• complement factor I deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Doyne honeycomb retinal dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• age related macular degeneration 13

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000285330 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000204.5
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000381 (58/152142) while in subpopulation NFE AF = 0.000838 (57/68032). AF 95% confidence interval is 0.000664. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000204.5. 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
	CFI	NM_000204.5	MANE Select	c.355G>A	p.Gly119Arg	missense	Exon 3 of 13	NP_000195.3
	CFI	NM_001375278.1		c.355G>A	p.Gly119Arg	missense	Exon 3 of 15	NP_001362207.1
	CFI	NM_001440985.1		c.355G>A	p.Gly119Arg	missense	Exon 3 of 15	NP_001427914.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFI	ENST00000394634.7	TSL:1 MANE Select	c.355G>A	p.Gly119Arg	missense	Exon 3 of 13	ENSP00000378130.2
	ENSG00000285330	ENST00000645635.1		c.355G>A	p.Gly119Arg	missense	Exon 3 of 15	ENSP00000493607.1
	CFI	ENST00000394635.8	TSL:2	c.355G>A	p.Gly119Arg	missense	Exon 3 of 14	ENSP00000378131.3

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

GnomAD2 exomes AF: 0.000422 AC: 106 AN: 251328 AF XY: 0.000456

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 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

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00102 AC: 1136 AN: 1111942

Other (OTH) AF: 0.000414 AC: 25 AN: 60390

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00102 Hom.: 2

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:4 Uncertain:6 Benign:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Benign:1

Feb 18, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Jul 19, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PS3, PS4_moderate

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 06, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

Jul 01, 2013

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

not specified Uncertain:2

Apr 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFI-related disorder Pathogenic:1

Sep 26, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

CFI p.Gly119Arg (c.355G>A) is a missense variant that changes the amino acid at residue 119 from Glycine to Arginine. This variant has been observed in at least one proband affected with a CFI-related disorder (PMID:35619721;23307876;30890598;27268256;34169201;23431077;33956337;37466676;22456601;20513133;28596415;27799617). At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:35069568;32510551;23685748). At least one splicing study identified that this variant results in aberrant splicing (PMID:39238643). In conclusion, we classify CFI p.Gly119Arg (c.355G>A) as a pathogenic variant.

Factor I deficiency Uncertain:1

May 28, 2021

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Kidney failure Uncertain:1

Feb 28, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Atypical hemolytic-uremic syndrome with I factor anomaly;C3463916:Factor I deficiency;C3809523:Age related macular degeneration 13 Uncertain:1

Feb 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Atypical hemolytic-uremic syndrome Uncertain:1

Feb 21, 2019

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jul 01, 2013

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.079
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		1.7
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.15	T
Polyphen		0.98	D
Vest4		0.40
MutPred		0.93		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
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs141853578; hg19: chr4-110685820;