rs10033900

Variant names:

• chr4-109737911-T-C
• rs10033900
• ENST00000645635.1:c.1534+4580A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001375278.1(CFI):​c.1559-3115A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.535 in 151,972 control chromosomes in the GnomAD database, including 21,995 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 0.53 (21995 hom., cov: 31)
• Consequence: CFI NM_001375278.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.63
• Publications: 130 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.61 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.1559-3115A>G		intron	N/A	NP_001362207.1
	CFI	NM_001440985.1		c.1556-3115A>G		intron	N/A	NP_001427914.1
	CFI	NM_001375279.1		c.1535-3115A>G		intron	N/A	NP_001362208.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000285330	ENST00000645635.1		c.1534+4580A>G		intron	N/A	ENSP00000493607.1	A0A2R8Y3M9
	CFI	ENST00000695844.1		n.1714-3115A>G		intron	N/A
	CFI	ENST00000695845.1		n.1712+4580A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81185 AN: 151852 Hom.: 21986 Cov.: 31

Gnomad AFR AF: 0.616

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.549

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

GnomAD4 genome AF: 0.535 AC: 81232 AN: 151972 Hom.: 21995 Cov.: 31 AF XY: 0.527 AC XY: 39168 AN XY: 74256

African (AFR) AF: 0.616 AC: 25558 AN: 41478

American (AMR) AF: 0.542 AC: 8266 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1769 AN: 3470

East Asian (EAS) AF: 0.383 AC: 1972 AN: 5152

South Asian (SAS) AF: 0.346 AC: 1663 AN: 4802

European-Finnish (FIN) AF: 0.462 AC: 4871 AN: 10550

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.519 AC: 35274 AN: 67946

Other (OTH) AF: 0.544 AC: 1147 AN: 2108

Alfa AF: 0.521 Hom.: 82814

Bravo AF: 0.547

Asia WGS AF: 0.335 AC: 1170 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.8
DANN	Benign	0.72
PhyloP100		1.6

Splicing

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

Other links and lift over

dbSNP: rs10033900; hg19: chr4-110659067;