rs113273712

Variant names:

• chr4-109752492-T-C
• rs113273712
• NM_000204.5:c.916A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000204.5(CFI):​c.916A>G​(p.Ile306Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000305 in 1,613,198 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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. I306S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: CFI NM_000204.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.290
• Publications: 3 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010314584).
• BP6: Variant 4-109752492-T-C is Benign according to our data. Variant chr4-109752492-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 347163.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 = 0.00152 (232/152230) while in subpopulation AFR AF = 0.00527 (219/41532). AF 95% confidence interval is 0.0047. There are 0 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.916A>G	p.Ile306Val	missense	Exon 8 of 13	NP_000195.3
	CFI	NM_001375278.1		c.940A>G	p.Ile314Val	missense	Exon 9 of 15	NP_001362207.1
	CFI	NM_001440985.1		c.937A>G	p.Ile313Val	missense	Exon 9 of 15	NP_001427914.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFI	ENST00000394634.7	TSL:1 MANE Select	c.916A>G	p.Ile306Val	missense	Exon 8 of 13	ENSP00000378130.2
	ENSG00000285330	ENST00000645635.1		c.916A>G	p.Ile306Val	missense	Exon 8 of 15	ENSP00000493607.1
	CFI	ENST00000394635.8	TSL:2	c.940A>G	p.Ile314Val	missense	Exon 9 of 14	ENSP00000378131.3

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 230 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00524

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000394 AC: 99 AN: 251238 AF XY: 0.000331

Gnomad AFR exome AF: 0.00505

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000178 AC: 260 AN: 1460968 Hom.: 1 Cov.: 29 AF XY: 0.000150 AC XY: 109 AN XY: 726806

African (AFR) AF: 0.00535 AC: 179 AN: 33456

American (AMR) AF: 0.000470 AC: 21 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39564

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111448

Other (OTH) AF: 0.000696 AC: 42 AN: 60350

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74448

African (AFR) AF: 0.00527 AC: 219 AN: 41532

American (AMR) AF: 0.000327 AC: 5 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68002

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.00164

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000478 AC: 58

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Atypical hemolytic-uremic syndrome with I factor anomaly (1)
-	-	1	CFI-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	2.9
DANN	Benign	0.70
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.29
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.070	N
REVEL	Uncertain	0.58
Sift	Benign	0.57	T
Sift4G	Benign	0.66	T
Polyphen		0.024	B
Vest4		0.069
MVP		0.36
MPC		0.060
ClinPred		0.17	T
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.062
gMVP		0.56
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		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: rs113273712; hg19: chr4-110673648;