rs114013791

Variant names:

• chr4-109742486-C-A
• rs114013791
• NM_000204.5:c.1534+5G>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001375278.1(CFI):​c.1558+5G>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0145 in 1,592,940 control chromosomes in the GnomAD database, including 240 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (7 hom., cov: 32)
  • Exomes 𝑓: 0.015 (233 hom.)
• Consequence: CFI NM_001375278.1 splice_region, intron
• Scores: Splicing: ADA: 0.8882
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.64
• Publications: 8 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 4-109742486-C-A is Benign according to our data. Variant chr4-109742486-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 252469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00914 (1392/152294) while in subpopulation NFE AF = 0.0162 (1105/68032). AF 95% confidence interval is 0.0154. There are 7 homozygotes in GnomAd4. There are 612 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375278.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFI	NM_000204.5	MANE Select	c.1534+5G>T		splice_region intron	N/A	NP_000195.3
	CFI	NM_001375278.1		c.1558+5G>T		splice_region intron	N/A	NP_001362207.1
	CFI	NM_001440985.1		c.1555+5G>T		splice_region intron	N/A	NP_001427914.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFI	ENST00000394634.7	TSL:1 MANE Select	c.1534+5G>T		splice_region intron	N/A	ENSP00000378130.2
	ENSG00000285330	ENST00000645635.1		c.1534+5G>T		splice_region intron	N/A	ENSP00000493607.1
	CFI	ENST00000963332.1		c.1624+5G>T		splice_region intron	N/A	ENSP00000633391.1

Frequencies

GnomAD3 genomes AF: 0.00915 AC: 1393 AN: 152176 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00311

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00632

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00863 AC: 2168 AN: 251162 AF XY: 0.00880

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00772

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.00735

GnomAD4 exome AF: 0.0150 AC: 21661 AN: 1440646 Hom.: 233 Cov.: 26 AF XY: 0.0147 AC XY: 10562 AN XY: 717978

African (AFR) AF: 0.00184 AC: 61 AN: 33064

American (AMR) AF: 0.00264 AC: 118 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00158 AC: 41 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.000955 AC: 82 AN: 85842

European-Finnish (FIN) AF: 0.00772 AC: 412 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0185 AC: 20212 AN: 1092674

Other (OTH) AF: 0.0123 AC: 735 AN: 59680

GnomAD4 genome AF: 0.00914 AC: 1392 AN: 152294 Hom.: 7 Cov.: 32 AF XY: 0.00822 AC XY: 612 AN XY: 74472

African (AFR) AF: 0.00308 AC: 128 AN: 41562

American (AMR) AF: 0.00301 AC: 46 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00632 AC: 67 AN: 10604

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0162 AC: 1105 AN: 68032

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.0142 Hom.: 25

Bravo AF: 0.00935

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0165

EpiControl AF: 0.0135

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Atypical hemolytic-uremic syndrome with I factor anomaly (2)
-	-	2	CFI-related disorder (2)
-	-	2	not provided (2)
-	-	1	Atypical hemolytic-uremic syndrome (1)
-	-	1	Atypical hemolytic-uremic syndrome with I factor anomaly;C3463916:Factor I deficiency;C3809523:Age related macular degeneration 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	33
DANN	Benign	0.96
PhyloP100		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Benign	0.62
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: -30

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

Other links and lift over

dbSNP: rs114013791; hg19: chr4-110663642;