4-109792808-A-G

Variant names:

• chr4-109792808-A-G
• rs10029485
• NM_000204.5:c.57+9107T>C

Variant summary

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

The NM_000204.5(CFI):​c.57+9107T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 151,750 control chromosomes in the GnomAD database, including 4,852 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 0.18 (4852 hom., cov: 32)
• Consequence: CFI NM_000204.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.792
• Publications: 4 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
• Doyne honeycomb retinal dystrophy

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

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

ENSG00000285330 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFI	NM_000204.5	c.57+9107T>C		intron_variant	Intron 1 of 12	ENST00000394634.7	NP_000195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFI	ENST00000394634.7	c.57+9107T>C		intron_variant	Intron 1 of 12	1	NM_000204.5	ENSP00000378130.2
ENSG00000285330	ENST00000645635.1	c.57+9107T>C		intron_variant	Intron 1 of 14			ENSP00000493607.1

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27663 AN: 151634 Hom.: 4837 Cov.: 32

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.0677

Gnomad EAS AF: 0.327

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.0883

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.0379

Gnomad OTH AF: 0.141

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

GnomAD4 genome AF: 0.183 AC: 27731 AN: 151750 Hom.: 4852 Cov.: 32 AF XY: 0.186 AC XY: 13797 AN XY: 74160

African (AFR) AF: 0.440 AC: 18193 AN: 41328

American (AMR) AF: 0.182 AC: 2784 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0677 AC: 235 AN: 3472

East Asian (EAS) AF: 0.328 AC: 1687 AN: 5150

South Asian (SAS) AF: 0.189 AC: 911 AN: 4810

European-Finnish (FIN) AF: 0.0883 AC: 927 AN: 10502

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 292

European-Non Finnish (NFE) AF: 0.0379 AC: 2573 AN: 67916

Other (OTH) AF: 0.142 AC: 300 AN: 2106

Alfa AF: 0.0631 Hom.: 1034

Bravo AF: 0.202

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.8
DANN	Benign	0.54
PhyloP100		-0.79
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: rs10029485; hg19: chr4-110713964;