4-109749651-G-C

Variant names:

• chr4-109749651-G-C
• rs7441380
• NM_000204.5:c.941-49C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001375278.1(CFI):​c.965-49C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.994 in 1,202,842 control chromosomes in the GnomAD database, including 594,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (72064 hom., cov: 32)
  • Exomes 𝑓: 1.0 (522125 hom.)
• Consequence: CFI NM_001375278.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.08
• Publications: 6 publications found

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
• Doyne honeycomb retinal dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• age related macular degeneration 13

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000285330 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-109749651-G-C is Benign according to our data. Variant chr4-109749651-G-C is described in ClinVar as Benign. ClinVar VariationId is 1209764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375278.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFI	NM_000204.5	MANE Select	c.941-49C>G		intron	N/A	NP_000195.3
	CFI	NM_001375278.1		c.965-49C>G		intron	N/A	NP_001362207.1
	CFI	NM_001440985.1		c.962-49C>G		intron	N/A	NP_001427914.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFI	ENST00000394634.7	TSL:1 MANE Select	c.941-49C>G		intron	N/A	ENSP00000378130.2
	ENSG00000285330	ENST00000645635.1		c.941-49C>G		intron	N/A	ENSP00000493607.1
	CFI	ENST00000963332.1		c.941-49C>G		intron	N/A	ENSP00000633391.1

Frequencies

GnomAD3 genomes AF: 0.972 AC: 147905 AN: 152184 Hom.: 72016 Cov.: 32

Gnomad AFR AF: 0.902

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.990

Gnomad ASJ AF: 0.995

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.984

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.980

GnomAD2 exomes AF: 0.993 AC: 244827 AN: 246632 AF XY: 0.995

Gnomad AFR exome AF: 0.900

Gnomad AMR exome AF: 0.996

Gnomad ASJ exome AF: 0.997

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.996

GnomAD4 exome AF: 0.997 AC: 1047263 AN: 1050540 Hom.: 522125 Cov.: 14 AF XY: 0.997 AC XY: 539621 AN XY: 541036

African (AFR) AF: 0.905 AC: 23204 AN: 25642

American (AMR) AF: 0.995 AC: 43830 AN: 44058

Ashkenazi Jewish (ASJ) AF: 0.997 AC: 23523 AN: 23590

East Asian (EAS) AF: 1.00 AC: 37758 AN: 37758

South Asian (SAS) AF: 1.00 AC: 77978 AN: 77992

European-Finnish (FIN) AF: 1.00 AC: 50340 AN: 50342

Middle Eastern (MID) AF: 0.991 AC: 4796 AN: 4840

European-Non Finnish (NFE) AF: 1.00 AC: 739360 AN: 739500

Other (OTH) AF: 0.993 AC: 46474 AN: 46818

GnomAD4 genome AF: 0.972 AC: 148010 AN: 152302 Hom.: 72064 Cov.: 32 AF XY: 0.972 AC XY: 72432 AN XY: 74482

African (AFR) AF: 0.902 AC: 37484 AN: 41538

American (AMR) AF: 0.990 AC: 15146 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 3456 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5184 AN: 5184

South Asian (SAS) AF: 1.00 AC: 4823 AN: 4824

European-Finnish (FIN) AF: 1.00 AC: 10622 AN: 10622

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68024 AN: 68048

Other (OTH) AF: 0.980 AC: 2074 AN: 2116

Alfa AF: 0.994 Hom.: 6897

Bravo AF: 0.967

Asia WGS AF: 0.994 AC: 3458 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CFI-related disorder (1)
-	-	1	Factor I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.54
DANN	Benign	0.24
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7441380; hg19: chr4-110670807;