rs6848178

Variant names:

• chr4-109745015-T-A
• rs6848178
• NM_000204.5:c.1429+1207A>T

Your query was ambiguous. Multiple possible variants found:

• chr4-109745015-T-A
• chr4-109745015-T-C
• chr4-109745015-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000204.5(CFI):​c.1429+1207A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 152,056 control chromosomes in the GnomAD database, including 23,089 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (23089 hom., cov: 32)
• Consequence: CFI NM_000204.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.75
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFI	NM_000204.5	c.1429+1207A>T		intron_variant	Intron 11 of 12	ENST00000394634.7	NP_000195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFI	ENST00000394634.7	c.1429+1207A>T		intron_variant	Intron 11 of 12	1	NM_000204.5	ENSP00000378130.2
ENSG00000285330	ENST00000645635.1	c.1429+1207A>T		intron_variant	Intron 11 of 14			ENSP00000493607.1

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82177 AN: 151938 Hom.: 23065 Cov.: 32

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.539

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.517

Gnomad EAS AF: 0.865

Gnomad SAS AF: 0.746

Gnomad FIN AF: 0.593

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.572

Gnomad OTH AF: 0.526

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

GnomAD4 genome AF: 0.541 AC: 82235 AN: 152056 Hom.: 23089 Cov.: 32 AF XY: 0.548 AC XY: 40743 AN XY: 74336

African (AFR) AF: 0.426 AC: 17671 AN: 41460

American (AMR) AF: 0.512 AC: 7825 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 1796 AN: 3472

East Asian (EAS) AF: 0.864 AC: 4478 AN: 5184

South Asian (SAS) AF: 0.747 AC: 3594 AN: 4812

European-Finnish (FIN) AF: 0.593 AC: 6259 AN: 10554

Middle Eastern (MID) AF: 0.455 AC: 133 AN: 292

European-Non Finnish (NFE) AF: 0.572 AC: 38869 AN: 67988

Other (OTH) AF: 0.531 AC: 1118 AN: 2104

Alfa AF: 0.551 Hom.: 2904

Bravo AF: 0.530

Asia WGS AF: 0.765 AC: 2660 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	12
DANN	Benign	0.76
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: rs6848178; hg19: chr4-110666171;