rs6854876

Variant names:

• chr4-109732284-C-G
• rs6854876
• ENST00000645635.1:c.1534+10207G>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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]

CFI Gene-Disease associations (from GenCC):

• atypical hemolytic-uremic syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• atypical hemolytic-uremic syndrome with I factor anomaly

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• complement factor I deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• C3 glomerulonephritis

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Doyne honeycomb retinal dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• age related macular degeneration 13

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375278.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFI	NM_001375278.1		c.1697-942G>C		intron	N/A	NP_001362207.1
	CFI	NM_001440985.1		c.1694-942G>C		intron	N/A	NP_001427914.1
	CFI	NM_001375279.1		c.1673-942G>C		intron	N/A	NP_001362208.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000285330	ENST00000645635.1		c.1534+10207G>C		intron	N/A	ENSP00000493607.1	A0A2R8Y3M9
	CFI	ENST00000695844.1		n.1852-942G>C		intron	N/A
	CFI	ENST00000695845.1		n.1713-942G>C		intron	N/A

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

African (AFR) AF: 0.816 AC: 33867 AN: 41510

American (AMR) AF: 0.518 AC: 7919 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1634 AN: 3470

East Asian (EAS) AF: 0.357 AC: 1844 AN: 5172

South Asian (SAS) AF: 0.563 AC: 2711 AN: 4814

European-Finnish (FIN) AF: 0.523 AC: 5521 AN: 10548

Middle Eastern (MID) AF: 0.476 AC: 139 AN: 292

European-Non Finnish (NFE) AF: 0.564 AC: 38322 AN: 67980

Other (OTH) AF: 0.575 AC: 1212 AN: 2106

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.0
DANN	Benign	0.67
PhyloP100		-0.064

Splicing

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

Other links and lift over

dbSNP: rs6854876; hg19: chr4-110653440;