NM_000204.5:c.1430-1730A>G

Variant names:

• chr4-109744325-T-C
• rs13104777
• NM_000204.5:c.1430-1730A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000204.5(CFI):​c.1430-1730A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 152,028 control chromosomes in the GnomAD database, including 10,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.35 (10295 hom., cov: 31)
• Consequence: CFI NM_000204.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.67
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 4-109744325-T-C is Benign according to our data. Variant chr4-109744325-T-C is described in ClinVar as Benign. ClinVar VariationId is 4280421.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.431 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFI	NM_000204.5	MANE Select	c.1430-1730A>G		intron	N/A	NP_000195.3
	CFI	NM_001375278.1		c.1454-1730A>G		intron	N/A	NP_001362207.1
	CFI	NM_001440985.1		c.1451-1730A>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.1430-1730A>G		intron	N/A	ENSP00000378130.2
	ENSG00000285330	ENST00000645635.1		c.1430-1730A>G		intron	N/A	ENSP00000493607.1
	CFI	ENST00000963332.1		c.1520-1730A>G		intron	N/A	ENSP00000633391.1

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52521 AN: 151910 Hom.: 10292 Cov.: 31

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.461

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.388

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.346 AC: 52537 AN: 152028 Hom.: 10295 Cov.: 31 AF XY: 0.345 AC XY: 25591 AN XY: 74284

African (AFR) AF: 0.170 AC: 7057 AN: 41472

American (AMR) AF: 0.440 AC: 6713 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1629 AN: 3468

East Asian (EAS) AF: 0.194 AC: 1005 AN: 5172

South Asian (SAS) AF: 0.252 AC: 1216 AN: 4826

European-Finnish (FIN) AF: 0.437 AC: 4605 AN: 10544

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.426 AC: 28937 AN: 67958

Other (OTH) AF: 0.384 AC: 811 AN: 2112

Alfa AF: 0.404 Hom.: 29460

Bravo AF: 0.338

Asia WGS AF: 0.226 AC: 787 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CFI-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Benign	0.95
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13104777; hg19: chr4-110665481;