rs28361433

Variant names:

• chr4-109740679-T-C
• rs28361433
• ENST00000645635.1:c.1534+1812A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001375278.1(CFI):​c.1558+1812A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 602,858 control chromosomes in the GnomAD database, including 333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (235 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (98 hom.)
• Consequence: CFI NM_001375278.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.962
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• complement factor I deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-109740679-T-C is Benign according to our data. Variant chr4-109740679-T-C is described in ClinVar as Benign. ClinVar VariationId is 369434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 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.1558+1812A>G		intron	N/A	NP_001362207.1
	CFI	NM_001440985.1		c.1555+1812A>G		intron	N/A	NP_001427914.1
	CFI	NM_001375279.1		c.1534+1812A>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+1812A>G		intron	N/A	ENSP00000493607.1	A0A2R8Y3M9
	CFI	ENST00000695844.1		n.1713+1812A>G		intron	N/A
	CFI	ENST00000695845.1		n.1712+1812A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 4808 AN: 152192 Hom.: 235 Cov.: 33

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.0229

GnomAD2 exomes AF: 0.0105 AC: 1051 AN: 100392 AF XY: 0.00860

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.0100

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.000119

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00926

GnomAD4 exome AF: 0.00599 AC: 2699 AN: 450548 Hom.: 98 Cov.: 4 AF XY: 0.00530 AC XY: 1294 AN XY: 244034

African (AFR) AF: 0.104 AC: 1267 AN: 12158

American (AMR) AF: 0.0115 AC: 235 AN: 20520

Ashkenazi Jewish (ASJ) AF: 0.0120 AC: 189 AN: 15714

East Asian (EAS) AF: 0.00 AC: 0 AN: 27288

South Asian (SAS) AF: 0.00211 AC: 111 AN: 52558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25474

Middle Eastern (MID) AF: 0.0401 AC: 100 AN: 2496

European-Non Finnish (NFE) AF: 0.00189 AC: 509 AN: 269098

Other (OTH) AF: 0.0114 AC: 288 AN: 25242

GnomAD4 genome AF: 0.0316 AC: 4814 AN: 152310 Hom.: 235 Cov.: 33 AF XY: 0.0305 AC XY: 2275 AN XY: 74482

African (AFR) AF: 0.104 AC: 4301 AN: 41540

American (AMR) AF: 0.0165 AC: 253 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00207 AC: 141 AN: 68034

Other (OTH) AF: 0.0227 AC: 48 AN: 2116

Alfa AF: 0.0241 Hom.: 28

Bravo AF: 0.0368

Asia WGS AF: 0.00780 AC: 28 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Atypical hemolytic-uremic syndrome with I factor anomaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.8
DANN	Benign	0.44
PhyloP100		0.96

Splicing

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

Other links and lift over

dbSNP: rs28361433; hg19: chr4-110661835;