rs998538

Positions:

• chr4-109787474-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000204.5(CFI):​c.57+14441G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 151,936 control chromosomes in the GnomAD database, including 1,792 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.10 (1792 hom., cov: 32)
• Consequence: CFI NM_000204.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.65

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFI	NM_000204.5	c.57+14441G>A		intron_variant		ENST00000394634.7	NP_000195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFI	ENST00000394634.7	c.57+14441G>A		intron_variant		1	NM_000204.5	ENSP00000378130	P2

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15497 AN: 151818 Hom.: 1786 Cov.: 32

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0710

Gnomad ASJ AF: 0.0567

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.0622

Gnomad FIN AF: 0.0260

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.0829

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.102 AC: 15527 AN: 151936 Hom.: 1792 Cov.: 32 AF XY: 0.101 AC XY: 7533 AN XY: 74274

Gnomad4 AFR AF: 0.279

Gnomad4 AMR AF: 0.0706

Gnomad4 ASJ AF: 0.0567

Gnomad4 EAS AF: 0.180

Gnomad4 SAS AF: 0.0623

Gnomad4 FIN AF: 0.0260

Gnomad4 NFE AF: 0.0136

Gnomad4 OTH AF: 0.0815

Alfa AF: 0.0625 Hom.: 100

Bravo AF: 0.116

Asia WGS AF: 0.119 AC: 411 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.22
DANN	Benign	0.69

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: rs998538; hg19: chr4-110708630;