4-109741002-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000204.5(CFI):ā€‹c.1643A>Gā€‹(p.Glu548Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E548Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

CFI
NM_000204.5 missense

Scores

6
10
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.20
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFINM_000204.5 linkuse as main transcriptc.1643A>G p.Glu548Gly missense_variant 13/13 ENST00000394634.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFIENST00000394634.7 linkuse as main transcriptc.1643A>G p.Glu548Gly missense_variant 13/131 NM_000204.5 P2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251308
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135806
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461862
Hom.:
0
Cov.:
33
AF XY:
0.00000550
AC XY:
4
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 17, 2023This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 548 of the CFI protein (p.Glu548Gly). This variant is present in population databases (rs771446070, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CFI-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFI protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Uncertain
0.013
T
BayesDel_noAF
Uncertain
-0.040
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.55
D;D;.
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.89
D;D;D
MetaSVM
Uncertain
0.58
D
MutationAssessor
Benign
1.4
L;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.36
T
PROVEAN
Pathogenic
-5.7
D;D;D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.0020
D;D;D
Sift4G
Uncertain
0.0030
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.64
MutPred
0.68
.;Loss of stability (P = 0.0539);.;
MVP
0.93
MPC
0.43
ClinPred
0.98
D
GERP RS
5.3
Varity_R
0.96
gMVP
0.84

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs771446070; hg19: chr4-110662158; API