rs114013791

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000204.5(CFI):c.1534+5G>T variant causes a splice donor 5th base, 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_000204.5 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.8882

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.64

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 252469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-109742486-C-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFI	NM_000204.5 linkuse as main transcript	c.1534+5G>T		splice_donor_5th_base_variant, intron_variant		ENST00000394634.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFI	ENST00000394634.7 linkuse as main transcript	c.1534+5G>T		splice_donor_5th_base_variant, intron_variant		1	NM_000204.5	P2

Frequencies

GnomAD3 genomes

AF:

0.00915

AC:

1393

AN:

152176

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00863

AC:

2168

AN:

251162

Hom.:

AF XY:

0.00880

AC XY:

1194

AN XY:

135754

show subpopulations

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 SAS exome

AF:

0.000784

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.:

AF XY:

0.0147

AC XY:

10562

AN XY:

717978

show subpopulations

Gnomad4 AFR exome

AF:

0.00184

Gnomad4 AMR exome

AF:

0.00264

Gnomad4 ASJ exome

AF:

0.00158

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000955

Gnomad4 FIN exome

AF:

0.00772

Gnomad4 NFE exome

AF:

0.0185

Gnomad4 OTH exome

AF:

0.0123

GnomAD4 genome

AF:

0.00914

AC:

1392

AN:

152294

Hom.:

Cov.:

AF XY:

0.00822

AC XY:

612

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00308

Gnomad4 AMR

AF:

0.00301

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00632

Gnomad4 NFE

AF:

0.0162

Gnomad4 OTH

AF:

0.00899

Alfa

AF:

0.0143

Hom.:

Bravo

AF:

0.00935

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0165

EpiControl

AF:

0.0135

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 130/13004=0.99%: in th eEur: 130/8598=1.5% -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 08, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Atypical hemolytic-uremic syndrome with I factor anomaly

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	CFI: BS1, BS2; ENSG00000285330: BS1, BS2 -

CFI-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 26, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Atypical hemolytic-uremic syndrome with I factor anomaly;C3463916:Factor I deficiency;C3809523:Age related macular degeneration 13

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 23, 2021

- -

Atypical hemolytic-uremic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.23

Cadd

Pathogenic

Dann

Benign

0.96

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over