rs10033900

chr4-109737911-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001375278.1(CFI):c.1559-3115A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.535 in 151,972 control chromosomes in the GnomAD database, including 21,995 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 0.53 (21995 hom., cov: 31)
• Consequence: CFI NM_001375278.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.63

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFI	NM_001375278.1	c.1559-3115A>G		intron_variant
CFI	NM_001375279.1	c.1535-3115A>G		intron_variant
CFI	NM_001375280.1	c.1514-3115A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFI	ENST00000695844.1	n.1714-3115A>G		intron_variant, non_coding_transcript_variant
CFI	ENST00000695845.1	n.1712+4580A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81185 AN: 151852 Hom.: 21986 Cov.: 31

Gnomad AFR AF: 0.616

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.549

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

GnomAD4 genome AF: 0.535 AC: 81232 AN: 151972 Hom.: 21995 Cov.: 31 AF XY: 0.527 AC XY: 39168 AN XY: 74256

Gnomad4 AFR AF: 0.616

Gnomad4 AMR AF: 0.542

Gnomad4 ASJ AF: 0.510

Gnomad4 EAS AF: 0.383

Gnomad4 SAS AF: 0.346

Gnomad4 FIN AF: 0.462

Gnomad4 NFE AF: 0.519

Gnomad4 OTH AF: 0.544

Alfa AF: 0.515 Hom.: 40859

Bravo AF: 0.547

Asia WGS AF: 0.335 AC: 1170 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	7.8
Dann	Benign	0.72

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10033900; hg19: chr4-110659067;