rs998538

Variant names:

• chr4-109787474-C-T
• rs998538
• NM_000204.5:c.57+14441G>A

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+14441G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 151,936 control chromosomes in the GnomAD database, including 1,792 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 0.10 (1792 hom., cov: 32)
• Consequence: CFI NM_000204.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.65
• Publications: 2 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFI	NM_000204.5	c.57+14441G>A		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+14441G>A		intron_variant	Intron 1 of 12	1	NM_000204.5	ENSP00000378130.2
ENSG00000285330	ENST00000645635.1	c.57+14441G>A		intron_variant	Intron 1 of 14			ENSP00000493607.1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15497 AN: 151818 Hom.: 1786 Cov.: 32

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0710

Gnomad ASJ AF: 0.0567

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.0622

Gnomad FIN AF: 0.0260

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.0829

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

GnomAD4 genome AF: 0.102 AC: 15527 AN: 151936 Hom.: 1792 Cov.: 32 AF XY: 0.101 AC XY: 7533 AN XY: 74274

African (AFR) AF: 0.279 AC: 11548 AN: 41382

American (AMR) AF: 0.0706 AC: 1076 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.0567 AC: 197 AN: 3472

East Asian (EAS) AF: 0.180 AC: 927 AN: 5150

South Asian (SAS) AF: 0.0623 AC: 300 AN: 4818

European-Finnish (FIN) AF: 0.0260 AC: 275 AN: 10590

Middle Eastern (MID) AF: 0.0788 AC: 23 AN: 292

European-Non Finnish (NFE) AF: 0.0136 AC: 923 AN: 67978

Other (OTH) AF: 0.0815 AC: 172 AN: 2110

Alfa AF: 0.0707 Hom.: 123

Bravo AF: 0.116

Asia WGS AF: 0.119 AC: 411 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.22
DANN	Benign	0.69
PhyloP100		-2.6
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: rs998538; hg19: chr4-110708630;