rs113460688

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_000204.5(CFI):c.1657C>T(p.Pro553Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,614,134 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 8 hom. )

Consequence

CFI
NM_000204.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.754

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008018434).

BP6

Variant 4-109740988-G-A is Benign according to our data. Variant chr4-109740988-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 347146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-109740988-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00127 (194/152292) while in subpopulation NFE AF= 0.00243 (165/68022). AF 95% confidence interval is 0.00212. There are 1 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFI	NM_000204.5 linkuse as main transcript	c.1657C>T	p.Pro553Ser	missense_variant	13/13	ENST00000394634.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFI	ENST00000394634.7 linkuse as main transcript	c.1657C>T	p.Pro553Ser	missense_variant	13/13	1	NM_000204.5	P2

Frequencies

GnomAD3 genomes

AF:

0.00127

AC:

194

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00243

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00135

AC:

339

AN:

251218

Hom.:

AF XY:

0.00144

AC XY:

196

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00269

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.00272

AC:

3983

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

1880

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000243

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.00335

Gnomad4 OTH exome

AF:

0.00301

GnomAD4 genome

AF:

0.00127

AC:

194

AN:

152292

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00243

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00204

Hom.:

Bravo

AF:

0.00131

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00127

AC:

154

EpiCase

AF:

0.00251

EpiControl

AF:

0.00273

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Atypical hemolytic-uremic syndrome with I factor anomaly

Benign:1

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

CFI-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2023

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

Cadd

Benign

Dann

Benign

0.95

DEOGEN2

Uncertain

0.55

D;D;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.38

T;T;T

M_CAP

Benign

0.056

MetaRNN

Benign

0.0080

T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.1

L;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Benign

0.17

Sift

Benign

0.28

T;T;T

Sift4G

Benign

0.34

T;T;T

Polyphen

0.25

B;B;B

Vest4

0.12

MVP

0.77

MPC

0.12

ClinPred

0.0083

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.26

gMVP

0.63

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

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