ENST00000645635.1:c.1534+4791G>C

Variant names:

• chr4-109737700-C-G
• rs13117504
• ENST00000645635.1:c.1534+4791G>C

Variant summary

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

The ENST00000645635.1(ENSG00000285330):​c.1534+4791G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 152,128 control chromosomes in the GnomAD database, including 11,774 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 0.37 (11774 hom., cov: 32)
• Consequence: ENSG00000285330 ENST00000645635.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.543
• Publications: 15 publications found

Genes affected

ENSG00000285330 (HGNC:):

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)

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 = 0.585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFI	NM_001375278.1	c.1559-2904G>C		intron_variant	Intron 13 of 14		NP_001362207.1
CFI	NM_001440985.1	c.1556-2904G>C		intron_variant	Intron 13 of 14		NP_001427914.1
CFI	NM_001375279.1	c.1535-2904G>C		intron_variant	Intron 12 of 13		NP_001362208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000285330	ENST00000645635.1	c.1534+4791G>C		intron_variant	Intron 12 of 14			ENSP00000493607.1
CFI	ENST00000695844.1	n.1714-2904G>C		intron_variant	Intron 12 of 13
CFI	ENST00000695845.1	n.1712+4791G>C		intron_variant	Intron 12 of 12

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56357 AN: 152010 Hom.: 11779 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.485

Gnomad EAS AF: 0.603

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.410

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

GnomAD4 genome AF: 0.370 AC: 56345 AN: 152128 Hom.: 11774 Cov.: 32 AF XY: 0.377 AC XY: 28071 AN XY: 74366

African (AFR) AF: 0.169 AC: 7019 AN: 41528

American (AMR) AF: 0.467 AC: 7135 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 1683 AN: 3470

East Asian (EAS) AF: 0.603 AC: 3126 AN: 5184

South Asian (SAS) AF: 0.423 AC: 2038 AN: 4822

European-Finnish (FIN) AF: 0.470 AC: 4956 AN: 10552

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.427 AC: 28997 AN: 67968

Other (OTH) AF: 0.406 AC: 859 AN: 2114

Alfa AF: 0.386 Hom.: 1508

Bravo AF: 0.365

Asia WGS AF: 0.469 AC: 1632 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.8
DANN	Benign	0.71
PhyloP100		0.54

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs13117504; hg19: chr4-110658856;