NM_000204.5:c.483-606C>T

Variant names:

• chr4-109762298-G-A
• rs7356506
• NM_000204.5:c.483-606C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000204.5(CFI):​c.483-606C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.639 in 152,238 control chromosomes in the GnomAD database, including 32,368 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.64 (32296 hom., cov: 31)
  • Exomes 𝑓: 0.64 (72 hom.)
• Consequence: CFI NM_000204.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.789
• Publications: 6 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 4-109762298-G-A is Benign according to our data. Variant chr4-109762298-G-A is described in ClinVar as Benign. ClinVar VariationId is 4280423.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFI	NM_000204.5	c.483-606C>T		intron_variant	Intron 3 of 12	ENST00000394634.7	NP_000195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFI	ENST00000394634.7	c.483-606C>T		intron_variant	Intron 3 of 12	1	NM_000204.5	ENSP00000378130.2
ENSG00000285330	ENST00000645635.1	c.483-606C>T		intron_variant	Intron 3 of 14			ENSP00000493607.1

Frequencies

GnomAD3 genomes AF: 0.639 AC: 96984 AN: 151806 Hom.: 32281 Cov.: 31

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.563

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.693

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.758

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.747

Gnomad OTH AF: 0.645

GnomAD4 exome AF: 0.636 AC: 201 AN: 316 Hom.: 72 Cov.: 0 AF XY: 0.603 AC XY: 111 AN XY: 184

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.571 AC: 8 AN: 14

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 4 AN: 4

East Asian (EAS) AF: 0.500 AC: 3 AN: 6

South Asian (SAS) AF: 1.00 AC: 2 AN: 2

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.635 AC: 179 AN: 282

Other (OTH) AF: 0.500 AC: 3 AN: 6

GnomAD4 genome AF: 0.639 AC: 97037 AN: 151922 Hom.: 32296 Cov.: 31 AF XY: 0.639 AC XY: 47451 AN XY: 74260

African (AFR) AF: 0.441 AC: 18262 AN: 41396

American (AMR) AF: 0.591 AC: 9019 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 2405 AN: 3468

East Asian (EAS) AF: 0.691 AC: 3571 AN: 5168

South Asian (SAS) AF: 0.758 AC: 3648 AN: 4812

European-Finnish (FIN) AF: 0.694 AC: 7321 AN: 10546

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.747 AC: 50764 AN: 67980

Other (OTH) AF: 0.650 AC: 1364 AN: 2100

Alfa AF: 0.724 Hom.: 25633

Bravo AF: 0.620

Asia WGS AF: 0.692 AC: 2409 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.2
DANN	Benign	0.34
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: rs7356506; hg19: chr4-110683454;