rs13104777

Positions:

• chr4-109744325-T-C

Variant summary

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

The NM_000204.5(CFI):​c.1430-1730A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 152,028 control chromosomes in the GnomAD database, including 10,295 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 0.35 (10295 hom., cov: 31)
• Consequence: CFI NM_000204.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.67

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=-0.48).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFI	NM_000204.5	c.1430-1730A>G		intron_variant		ENST00000394634.7	NP_000195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFI	ENST00000394634.7	c.1430-1730A>G		intron_variant		1	NM_000204.5	ENSP00000378130	P2

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52521 AN: 151910 Hom.: 10292 Cov.: 31

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.461

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.388

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

GnomAD4 genome AF: 0.346 AC: 52537 AN: 152028 Hom.: 10295 Cov.: 31 AF XY: 0.345 AC XY: 25591 AN XY: 74284

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.440

Gnomad4 ASJ AF: 0.470

Gnomad4 EAS AF: 0.194

Gnomad4 SAS AF: 0.252

Gnomad4 FIN AF: 0.437

Gnomad4 NFE AF: 0.426

Gnomad4 OTH AF: 0.384

Alfa AF: 0.411 Hom.: 23528

Bravo AF: 0.338

Asia WGS AF: 0.226 AC: 787 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Benign	0.95

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: rs13104777; hg19: chr4-110665481;