rs12512308

Positions:

• chr4-109771075-G-A

Variant summary

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

The NM_000204.5(CFI):​c.58-4251C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 151,878 control chromosomes in the GnomAD database, including 5,035 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 0.24 (5035 hom., cov: 30)
• Consequence: CFI NM_000204.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.358

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=-0.74).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFI	NM_000204.5	c.58-4251C>T		intron_variant		ENST00000394634.7	NP_000195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFI	ENST00000394634.7	c.58-4251C>T		intron_variant		1	NM_000204.5	ENSP00000378130	P2

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36578 AN: 151760 Hom.: 5032 Cov.: 30

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.274

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

GnomAD4 genome AF: 0.241 AC: 36584 AN: 151878 Hom.: 5035 Cov.: 30 AF XY: 0.244 AC XY: 18101 AN XY: 74188

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.355

Gnomad4 ASJ AF: 0.289

Gnomad4 EAS AF: 0.255

Gnomad4 SAS AF: 0.236

Gnomad4 FIN AF: 0.313

Gnomad4 NFE AF: 0.276

Gnomad4 OTH AF: 0.274

Alfa AF: 0.273 Hom.: 790

Bravo AF: 0.242

Asia WGS AF: 0.268 AC: 933 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.79

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: rs12512308; hg19: chr4-110692231;