4-109760462-C-T

Variant names:

• chr4-109760462-C-T
• rs4382037
• NM_000204.5:c.772+61G>A

Variant summary

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

The NM_000204.5(CFI):​c.772+61G>A 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 1,500,260 control chromosomes in the GnomAD database, including 741,645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71795 hom., cov: 33)
  • Exomes 𝑓: 1.0 (669850 hom.)
• Consequence: CFI NM_000204.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.725
• Publications: 8 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=-0.99).
• BP6: Variant 4-109760462-C-T is Benign according to our data. Variant chr4-109760462-C-T is described in ClinVar as Benign. ClinVar VariationId is 1209766.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFI	NM_000204.5	c.772+61G>A		intron_variant	Intron 5 of 12	ENST00000394634.7	NP_000195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFI	ENST00000394634.7	c.772+61G>A		intron_variant	Intron 5 of 12	1	NM_000204.5	ENSP00000378130.2
ENSG00000285330	ENST00000645635.1	c.772+61G>A		intron_variant	Intron 5 of 14			ENSP00000493607.1

Frequencies

GnomAD3 genomes AF: 0.970 AC: 147618 AN: 152206 Hom.: 71748 Cov.: 33

Gnomad AFR AF: 0.896

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.989

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: 0.979

GnomAD4 exome AF: 0.997 AC: 1343622 AN: 1347936 Hom.: 669850 Cov.: 20 AF XY: 0.997 AC XY: 675139 AN XY: 677024

African (AFR) AF: 0.895 AC: 27706 AN: 30948

American (AMR) AF: 0.994 AC: 44214 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.997 AC: 25324 AN: 25390

East Asian (EAS) AF: 1.00 AC: 39154 AN: 39154

South Asian (SAS) AF: 1.00 AC: 83908 AN: 83934

European-Finnish (FIN) AF: 1.00 AC: 53340 AN: 53340

Middle Eastern (MID) AF: 0.990 AC: 5503 AN: 5556

European-Non Finnish (NFE) AF: 1.00 AC: 1008334 AN: 1008554

Other (OTH) AF: 0.992 AC: 56139 AN: 56576

GnomAD4 genome AF: 0.970 AC: 147722 AN: 152324 Hom.: 71795 Cov.: 33 AF XY: 0.970 AC XY: 72288 AN XY: 74492

African (AFR) AF: 0.896 AC: 37216 AN: 41554

American (AMR) AF: 0.989 AC: 15134 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 3454 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5190 AN: 5190

South Asian (SAS) AF: 1.00 AC: 4818 AN: 4820

European-Finnish (FIN) AF: 1.00 AC: 10627 AN: 10628

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

European-Non Finnish (NFE) AF: 1.00 AC: 68011 AN: 68038

Other (OTH) AF: 0.979 AC: 2071 AN: 2116

Alfa AF: 0.975 Hom.: 9541

Bravo AF: 0.965

Asia WGS AF: 0.993 AC: 3455 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Factor I deficiency Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.065
DANN	Benign	0.20
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4382037; hg19: chr4-110681618;