rs112534524

chr4-109760371-C-Gchr4-109760371-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000204.5(CFI):c.782G>C(p.Gly261Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G261D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CFI NM_000204.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0800

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15564719).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFI	NM_000204.5	c.782G>C	p.Gly261Ala	missense_variant	6/13	ENST00000394634.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFI	ENST00000394634.7	c.782G>C	p.Gly261Ala	missense_variant	6/13	1	NM_000204.5	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	9.4
Dann	Benign	0.96
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.84	T;T;T;T;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
Polyphen		0.70, 0.85, 0.065	.;P;P;.;B
Vest4		0.22, 0.24, 0.28, 0.22
MutPred		0.55		Loss of glycosylation at K262 (P = 0.0684);Loss of glycosylation at K262 (P = 0.0684);Loss of glycosylation at K262 (P = 0.0684);Loss of glycosylation at K262 (P = 0.0684);Loss of glycosylation at K262 (P = 0.0684);
MVP		0.76
MPC		0.13
ClinPred		0.29	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.48

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: rs112534524; hg19: chr4-110681527;