4-109757846-G-T

Variant names:

• chr4-109757846-G-T
• rs7437142
• NM_000204.5:c.884-63C>A

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.908-63C>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 1,342,580 control chromosomes in the GnomAD database, including 663,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71695 hom., cov: 31)
  • Exomes 𝑓: 1.0 (591479 hom.)
• Consequence: CFI NM_001375278.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.697
• Publications: 5 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 4-109757846-G-T is Benign according to our data. Variant chr4-109757846-G-T is described in ClinVar as Benign. ClinVar VariationId is 1209765.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFI	NM_000204.5	MANE Select	c.884-63C>A		intron	N/A	NP_000195.3
	CFI	NM_001375278.1		c.908-63C>A		intron	N/A	NP_001362207.1
	CFI	NM_001440985.1		c.905-63C>A		intron	N/A	NP_001427914.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFI	ENST00000394634.7	TSL:1 MANE Select	c.884-63C>A		intron	N/A	ENSP00000378130.2
	ENSG00000285330	ENST00000645635.1		c.884-63C>A		intron	N/A	ENSP00000493607.1
	CFI	ENST00000963332.1		c.884-63C>A		intron	N/A	ENSP00000633391.1

Frequencies

GnomAD3 genomes AF: 0.970 AC: 147405 AN: 151972 Hom.: 71648 Cov.: 31

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: 0.978

GnomAD4 exome AF: 0.997 AC: 1186533 AN: 1190490 Hom.: 591479 Cov.: 17 AF XY: 0.997 AC XY: 596421 AN XY: 598154

African (AFR) AF: 0.890 AC: 24123 AN: 27094

American (AMR) AF: 0.993 AC: 36231 AN: 36472

Ashkenazi Jewish (ASJ) AF: 0.997 AC: 23122 AN: 23190

East Asian (EAS) AF: 1.00 AC: 36144 AN: 36144

South Asian (SAS) AF: 1.00 AC: 74950 AN: 74976

European-Finnish (FIN) AF: 1.00 AC: 48924 AN: 48924

Middle Eastern (MID) AF: 0.990 AC: 4924 AN: 4976

European-Non Finnish (NFE) AF: 1.00 AC: 888143 AN: 888330

Other (OTH) AF: 0.992 AC: 49972 AN: 50384

GnomAD4 genome AF: 0.970 AC: 147509 AN: 152090 Hom.: 71695 Cov.: 31 AF XY: 0.971 AC XY: 72184 AN XY: 74378

African (AFR) AF: 0.896 AC: 37094 AN: 41412

American (AMR) AF: 0.989 AC: 15108 AN: 15276

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

East Asian (EAS) AF: 1.00 AC: 5180 AN: 5180

South Asian (SAS) AF: 1.00 AC: 4824 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10572 AN: 10572

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

European-Non Finnish (NFE) AF: 1.00 AC: 68009 AN: 68036

Other (OTH) AF: 0.979 AC: 2065 AN: 2110

Alfa AF: 0.974 Hom.: 10051

Bravo AF: 0.965

Asia WGS AF: 0.993 AC: 3437 AN: 3460

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.56
DANN	Benign	0.36
PhyloP100		-0.70
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: rs7437142; hg19: chr4-110679002;