rs6854876

Positions:

• chr4-109732284-C-G
• chr4-109732284-C-T

Variant summary

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

The NM_001375278.1(CFI):​c.1697-942G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 152,078 control chromosomes in the GnomAD database, including 30,135 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 0.62 (30135 hom., cov: 32)
• Consequence: CFI NM_001375278.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0640

Genes affected

ENSG00000285330 (HGNC:):

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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFI	NM_001375278.1	c.1697-942G>C		intron_variant			NP_001362207.1
CFI	NM_001375279.1	c.1673-942G>C		intron_variant			NP_001362208.1
CFI	NM_001375280.1	c.1652-942G>C		intron_variant			NP_001362209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000285330	ENST00000645635.1	c.1534+10207G>C		intron_variant				ENSP00000493607.1
CFI	ENST00000695844.1	n.1852-942G>C		intron_variant
CFI	ENST00000695845.1	n.1713-942G>C		intron_variant

Frequencies

GnomAD3 genomes AF: 0.616 AC: 93557 AN: 151962 Hom.: 30070 Cov.: 32

Gnomad AFR AF: 0.816

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.357

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.564

Gnomad OTH AF: 0.572

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

GnomAD4 genome AF: 0.616 AC: 93682 AN: 152078 Hom.: 30135 Cov.: 32 AF XY: 0.609 AC XY: 45281 AN XY: 74334

Gnomad4 AFR AF: 0.816

Gnomad4 AMR AF: 0.518

Gnomad4 ASJ AF: 0.471

Gnomad4 EAS AF: 0.357

Gnomad4 SAS AF: 0.563

Gnomad4 FIN AF: 0.523

Gnomad4 NFE AF: 0.564

Gnomad4 OTH AF: 0.575

Alfa AF: 0.462 Hom.: 1221

Bravo AF: 0.620

Asia WGS AF: 0.514 AC: 1785 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.0
DANN	Benign	0.67

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6854876; hg19: chr4-110653440;