NM_000204.5:c.482+6C>T

Variant names:

• chr4-109764531-G-A
• rs79375065
• NM_000204.5:c.482+6C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000204.5(CFI):​c.482+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00931 in 1,613,760 control chromosomes in the GnomAD database, including 491 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (265 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (226 hom.)
• Consequence: CFI NM_000204.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002120
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.452

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]

ENSG00000285330 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-109764531-G-A is Benign according to our data. Variant chr4-109764531-G-A is described in ClinVar as [Benign]. Clinvar id is 347171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-109764531-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFI	NM_000204.5	c.482+6C>T		splice_region_variant, 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.482+6C>T		splice_region_variant, intron_variant	Intron 3 of 12	1	NM_000204.5	ENSP00000378130.2
ENSG00000285330	ENST00000645635.1	c.482+6C>T		splice_region_variant, intron_variant	Intron 3 of 14			ENSP00000493607.1

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5081 AN: 152028 Hom.: 263 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0187

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000567

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00384

Gnomad OTH AF: 0.0311

GnomAD3 exomes AF: 0.0113 AC: 2851 AN: 251368 Hom.: 101 AF XY: 0.00888 AC XY: 1207 AN XY: 135860

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.0155

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.000696

Gnomad NFE exome AF: 0.00373

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.00678 AC: 9911 AN: 1461614 Hom.: 226 Cov.: 31 AF XY: 0.00647 AC XY: 4703 AN XY: 727130

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.0125

Gnomad4 ASJ exome AF: 0.0172

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000754

Gnomad4 FIN exome AF: 0.000676

Gnomad4 NFE exome AF: 0.00382

Gnomad4 OTH exome AF: 0.0124

GnomAD4 genome AF: 0.0336 AC: 5108 AN: 152146 Hom.: 265 Cov.: 32 AF XY: 0.0327 AC XY: 2430 AN XY: 74370

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000567

Gnomad4 NFE AF: 0.00384

Gnomad4 OTH AF: 0.0308

Alfa AF: 0.00557 Hom.: 3

Bravo AF: 0.0395

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 09, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27268256, 29292855) -

not specified Benign:2

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Atypical hemolytic-uremic syndrome with I factor anomaly Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Atypical hemolytic-uremic syndrome Benign:1

Aug 10, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.2
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs79375065; hg19: chr4-110685687;