4-109764531-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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:8

Conservation

PhyloP100: 0.452

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

atypical hemolytic-uremic syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
atypical hemolytic-uremic syndrome with I factor anomaly
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
complement factor I deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
C3 glomerulonephritis
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
Doyne honeycomb retinal dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
age related macular degeneration 13
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

CFI links:

ENSG00000285330 (HGNC:):

ENSG00000285330 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 347171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000204.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CFI	NM_000204.5	MANE Select	c.482+6C>T	splice_region intron	N/A	NP_000195.3	P05156
CFI	NM_001375278.1		c.482+6C>T	splice_region intron	N/A	NP_001362207.1
CFI	NM_001440985.1		c.482+6C>T	splice_region intron	N/A	NP_001427914.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CFI	ENST00000394634.7	TSL:1 MANE Select	c.482+6C>T	splice_region intron	N/A	ENSP00000378130.2	P05156
ENSG00000285330	ENST00000645635.1		c.482+6C>T	splice_region intron	N/A	ENSP00000493607.1	A0A2R8Y3M9
CFI	ENST00000510800.1	TSL:2	c.*2C>T	3_prime_UTR	Exon 3 of 3	ENSP00000422009.1	D6R9Z8

Frequencies

GnomAD3 genomes

AF:

0.0334

AC:

5081

AN:

152028

Hom.:

263

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0113

AC:

2851

AN:

251368

AF XY:

0.00888

show subpopulations

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 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.:

AF XY:

0.00647

AC XY:

4703

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.109

AC:

3647

AN:

33476

American (AMR)

AF:

0.0125

AC:

557

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0172

AC:

449

AN:

26130

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39686

South Asian (SAS)

AF:

0.000754

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000676

AC:

AN:

53272

Middle Eastern (MID)

AF:

0.0276

AC:

159

AN:

5768

European-Non Finnish (NFE)

AF:

0.00382

AC:

4248

AN:

1111912

Other (OTH)

AF:

0.0124

AC:

747

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

466

933

1399

1866

2332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

234

468

702

936

1170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0336

AC:

5108

AN:

152146

Hom.:

265

Cov.:

AF XY:

0.0327

AC XY:

2430

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.106

AC:

4380

AN:

41490

American (AMR)

AF:

0.0186

AC:

285

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000830

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000567

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00384

AC:

261

AN:

68004

Other (OTH)

AF:

0.0308

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

233

466

698

931

1164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00557

Hom.:

Bravo

AF:

0.0395

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Atypical hemolytic-uremic syndrome (1)

Atypical hemolytic-uremic syndrome with I factor anomaly (1)

CFI-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.2

(source)

DANN

Benign

0.77

PhyloP100

0.45

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=85/15

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over