4-109760371-C-T

Position:

chr4-109760371-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000204.5(CFI):c.782G>A(p.Gly261Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,613,380 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G261S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 4 hom. )

Consequence

CFI
NM_000204.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 0.0800

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:

ENSG00000285330 (HGNC:):

ENSG00000285330 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007196605).

BP6

Variant 4-109760371-C-T is Benign according to our data. Variant chr4-109760371-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 65580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-109760371-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00148 (226/152314) while in subpopulation NFE AF= 0.00229 (156/68012). AF 95% confidence interval is 0.002. There are 0 homozygotes in gnomad4. There are 93 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFI	NM_000204.5 linkuse as main transcript	c.782G>A	p.Gly261Asp	missense_variant	6/13	ENST00000394634.7	NP_000195.3	P05156A8K3L0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFI	ENST00000394634.7 linkuse as main transcript	c.782G>A	p.Gly261Asp	missense_variant	6/13	1	NM_000204.5	ENSP00000378130.2		P05156
ENSG00000285330	ENST00000645635.1 linkuse as main transcript	c.782G>A	p.Gly261Asp	missense_variant	6/15			ENSP00000493607.1		A0A2R8Y3M9

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

226

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00229

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00136

AC:

342

AN:

251422

Hom.:

AF XY:

0.00131

AC XY:

178

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00456

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00191

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00230

AC:

3361

AN:

1461066

Hom.:

Cov.:

AF XY:

0.00235

AC XY:

1706

AN XY:

726874

show subpopulations

Gnomad4 AFR exome

AF:

0.000598

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.00532

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000394

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.00267

Gnomad4 OTH exome

AF:

0.00179

GnomAD4 genome

AF:

0.00148

AC:

226

AN:

152314

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00229

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00254

Hom.:

Bravo

AF:

0.00153

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00133

AC:

161

ClinVar

Significance: Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	CFI: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Atypical hemolytic-uremic syndrome with I factor anomaly

Benign:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
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. -

CFI-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 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). -

Chronic kidney disease

Benign:1

Likely benign, criteria provided, single submitter

research

Cavalleri Lab, Royal College of Surgeons in Ireland

May 28, 2020

PP3, BP6, BS1 -

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

Apr 06, 2022

- -

Atypical hemolytic-uremic syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

4.3

DANN

Benign

0.87

DEOGEN2

Uncertain

0.50

.;T;T;T;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.43

T;T;T;T;T

M_CAP

Benign

0.076

MetaRNN

Benign

0.0072

T;T;T;T;T

MetaSVM

Benign

-0.29

MutationAssessor

Benign

0.54

.;N;.;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.3

.;N;N;.;N

REVEL

Benign

0.23

Sift

Benign

0.14

.;T;T;.;T

Sift4G

Benign

0.12

.;T;T;T;T

Polyphen

0.075, 0.074, 0.036

.;B;B;.;B

Vest4

0.30, 0.67, 0.38, 0.51

MVP

0.76

MPC

0.11

ClinPred

0.0024

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.51

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