4-109760371-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

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 Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (4 hom.)
• Consequence: CFI NM_000204.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.0800

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 -16 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFI	NM_000204.5	c.782G>A	p.Gly261Asp	missense_variant	6/13	ENST00000394634.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFI	ENST00000394634.7	c.782G>A	p.Gly261Asp	missense_variant	6/13	1	NM_000204.5	P2

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 226 AN: 152196 Hom.: 0 Cov.: 33

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.: 0 AF XY: 0.00131 AC XY: 178 AN XY: 135874

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.: 4 Cov.: 32 AF XY: 0.00235 AC XY: 1706 AN XY: 726874

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.: 0 Cov.: 33 AF XY: 0.00125 AC XY: 93 AN XY: 74488

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.: 1

Bravo AF: 0.00153

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00133 AC: 161

ClinVar

Significance: Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CFI: BP4 -
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+	-	- -

Atypical hemolytic-uremic syndrome with I factor anomaly Benign:1 Other: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, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	4.3
Dann	Benign	0.87
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.43	T;T;T;T;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.0072	T;T;T;T;T
MetaSVM	Benign	-0.29	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	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	T
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

Other links and lift over

dbSNP: rs112534524; hg19: chr4-110681527;