rs551

Positions:

• chr4-109740781-G-A
• chr4-109740781-G-C
• chr4-109740781-G-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.*112C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.988 in 976,168 control chromosomes in the GnomAD database, including 477,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (69571 hom., cov: 33)
  • Exomes 𝑓: 0.99 (407695 hom.)
• Consequence: CFI NM_000204.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.456

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 4-109740781-G-A is Benign according to our data. Variant chr4-109740781-G-A is described in ClinVar as [Benign]. Clinvar id is 347143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-109740781-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFI	NM_000204.5	c.*112C>T		3_prime_UTR_variant	13/13	ENST00000394634.7	NP_000195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFI	ENST00000394634.7	c.*112C>T		3_prime_UTR_variant	13/13	1	NM_000204.5	ENSP00000378130	P2

Frequencies

GnomAD3 genomes AF: 0.953 AC: 145054 AN: 152196 Hom.: 69515 Cov.: 33

Gnomad AFR AF: 0.837

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.982

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.965

GnomAD3 exomes AF: 0.989 AC: 177694 AN: 179620 Hom.: 88015 AF XY: 0.992 AC XY: 97595 AN XY: 98392

Gnomad AFR exome AF: 0.838

Gnomad AMR exome AF: 0.991

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.992

GnomAD4 exome AF: 0.995 AC: 819323 AN: 823854 Hom.: 407695 Cov.: 11 AF XY: 0.995 AC XY: 429548 AN XY: 431490

Gnomad4 AFR exome AF: 0.839

Gnomad4 AMR exome AF: 0.990

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.987

GnomAD4 genome AF: 0.953 AC: 145166 AN: 152314 Hom.: 69571 Cov.: 33 AF XY: 0.955 AC XY: 71108 AN XY: 74478

Gnomad4 AFR AF: 0.837

Gnomad4 AMR AF: 0.982

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.965

Alfa AF: 0.986 Hom.: 70677

Bravo AF: 0.947

Asia WGS AF: 0.989 AC: 3439 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Factor I deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.16
DANN	Benign	0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs551; hg19: chr4-110661937;