NM_000204.5:c.1429+1086C>T

Variant names:

• chr4-109745136-G-A
• rs6822976
• NM_000204.5:c.1429+1086C>T

Variant summary

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

The NM_000204.5(CFI):​c.1429+1086C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 152,098 control chromosomes in the GnomAD database, including 14,584 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 0.42 (14584 hom., cov: 33)
• Consequence: CFI NM_000204.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.103
• Publications: 7 publications found

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]

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

ENSG00000285330 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000204.5. 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_000204.5	MANE Select	c.1429+1086C>T		intron	N/A	NP_000195.3	P05156
	CFI	NM_001375278.1		c.1453+1086C>T		intron	N/A	NP_001362207.1
	CFI	NM_001440985.1		c.1450+1086C>T		intron	N/A	NP_001427914.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFI	ENST00000394634.7	TSL:1 MANE Select	c.1429+1086C>T		intron	N/A	ENSP00000378130.2	P05156
	ENSG00000285330	ENST00000645635.1		c.1429+1086C>T		intron	N/A	ENSP00000493607.1	A0A2R8Y3M9
	CFI	ENST00000963332.1		c.1519+1086C>T		intron	N/A	ENSP00000633391.1

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63513 AN: 151980 Hom.: 14578 Cov.: 33

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.620

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.495

Gnomad OTH AF: 0.430

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

GnomAD4 genome AF: 0.418 AC: 63546 AN: 152098 Hom.: 14584 Cov.: 33 AF XY: 0.423 AC XY: 31411 AN XY: 74342

African (AFR) AF: 0.220 AC: 9117 AN: 41488

American (AMR) AF: 0.449 AC: 6867 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1555 AN: 3470

East Asian (EAS) AF: 0.619 AC: 3205 AN: 5178

South Asian (SAS) AF: 0.537 AC: 2589 AN: 4824

European-Finnish (FIN) AF: 0.488 AC: 5153 AN: 10558

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.495 AC: 33654 AN: 67990

Other (OTH) AF: 0.433 AC: 912 AN: 2106

Alfa AF: 0.475 Hom.: 37069

Bravo AF: 0.407

Asia WGS AF: 0.527 AC: 1835 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.5
DANN	Benign	0.77
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6822976; hg19: chr4-110666292;