4-109743474-T-C

Variant names:

• chr4-109743474-T-C
• rs11726949
• NM_000204.5:c.1430-879A>G

Variant summary

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

The NM_000204.5(CFI):​c.1430-879A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.807 in 152,110 control chromosomes in the GnomAD database, including 52,372 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 0.81 (52372 hom., cov: 31)
• Consequence: CFI NM_000204.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.841
• Publications: 10 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFI	NM_000204.5	c.1430-879A>G		intron_variant	Intron 11 of 12	ENST00000394634.7	NP_000195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFI	ENST00000394634.7	c.1430-879A>G		intron_variant	Intron 11 of 12	1	NM_000204.5	ENSP00000378130.2
ENSG00000285330	ENST00000645635.1	c.1430-879A>G		intron_variant	Intron 11 of 14			ENSP00000493607.1

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122661 AN: 151992 Hom.: 52358 Cov.: 31

Gnomad AFR AF: 0.498

Gnomad AMI AF: 0.977

Gnomad AMR AF: 0.911

Gnomad ASJ AF: 0.923

Gnomad EAS AF: 0.850

Gnomad SAS AF: 0.845

Gnomad FIN AF: 0.942

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.934

Gnomad OTH AF: 0.851

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

GnomAD4 genome AF: 0.807 AC: 122709 AN: 152110 Hom.: 52372 Cov.: 31 AF XY: 0.810 AC XY: 60193 AN XY: 74358

African (AFR) AF: 0.497 AC: 20611 AN: 41436

American (AMR) AF: 0.912 AC: 13942 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.923 AC: 3202 AN: 3470

East Asian (EAS) AF: 0.850 AC: 4385 AN: 5156

South Asian (SAS) AF: 0.846 AC: 4079 AN: 4824

European-Finnish (FIN) AF: 0.942 AC: 9981 AN: 10594

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.934 AC: 63563 AN: 68022

Other (OTH) AF: 0.849 AC: 1791 AN: 2110

Alfa AF: 0.906 Hom.: 132297

Bravo AF: 0.792

Asia WGS AF: 0.801 AC: 2784 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.54
DANN	Benign	0.59
PhyloP100		-0.84
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: rs11726949; hg19: chr4-110664630;