dbSNP rs77449037: CFI:c.*144T>C (chr4-109740749-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000204.5(CFI):c.*144T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 799,092 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0078 ( 15 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 9 hom. )

Consequence

CFI
NM_000204.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.03

Publications

0 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=-0.82).

BP6

Variant 4-109740749-A-G is Benign according to our data. Variant chr4-109740749-A-G is described in ClinVar as Benign. ClinVar VariationId is 347142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00784 (1194/152380) while in subpopulation AFR AF = 0.0271 (1128/41594). AF 95% confidence interval is 0.0258. There are 15 homozygotes in GnomAd4. There are 556 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AD,Unknown,AR gene

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.*144T>C	3_prime_UTR	Exon 13 of 13	NP_000195.3	P05156
CFI	NM_001318057.2		c.*144T>C	3_prime_UTR	Exon 14 of 14	NP_001304986.2	E7ETH0
CFI	NM_001440986.1		c.*144T>C	3_prime_UTR	Exon 14 of 14	NP_001427915.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CFI	ENST00000394634.7	TSL:1 MANE Select	c.*144T>C	3_prime_UTR	Exon 13 of 13	ENSP00000378130.2	P05156
ENSG00000285330	ENST00000645635.1		c.1534+1742T>C	intron	N/A	ENSP00000493607.1	A0A2R8Y3M9
CFI	ENST00000963332.1		c.*144T>C	3_prime_UTR	Exon 14 of 14	ENSP00000633391.1

Frequencies

GnomAD3 genomes

AF:

0.00784

AC:

1193

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0272

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00192

AC:

277

AN:

144520

AF XY:

0.00167

show subpopulations

Gnomad AFR exome

AF:

0.0262

Gnomad AMR exome

AF:

0.00264

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000118

Gnomad OTH exome

AF:

0.00309

GnomAD4 exome

AF:

0.00104

AC:

673

AN:

646712

Hom.:

Cov.:

AF XY:

0.000915

AC XY:

315

AN XY:

344116

show subpopulations

African (AFR)

AF:

0.0271

AC:

461

AN:

17006

American (AMR)

AF:

0.00294

AC:

AN:

33296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20308

East Asian (EAS)

AF:

0.000185

AC:

AN:

32382

South Asian (SAS)

AF:

0.0000949

AC:

AN:

63196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35486

Middle Eastern (MID)

AF:

0.00119

AC:

AN:

4202

European-Non Finnish (NFE)

AF:

0.0000417

AC:

AN:

407340

Other (OTH)

AF:

0.00239

AC:

AN:

33496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

132

165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00784

AC:

1194

AN:

152380

Hom.:

Cov.:

AF XY:

0.00746

AC XY:

556

AN XY:

74528

show subpopulations

African (AFR)

AF:

0.0271

AC:

1128

AN:

41594

American (AMR)

AF:

0.00314

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68044

Other (OTH)

AF:

0.00710

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

121

181

242

302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00458

Hom.:

Bravo

AF:

0.00946

Asia WGS

AF:

0.00173

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

CFI-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

3.8

(source)

DANN

Benign

0.75

PhyloP100

1.0

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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