rs7439493

Variant names:

• chr4-109735574-G-A
• rs7439493
• ENST00000645635.1:c.1534+6917C>T

Variant summary

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

The ENST00000645635.1(ENSG00000285330):​c.1534+6917C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 152,096 control chromosomes in the GnomAD database, including 11,265 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 0.36 (11265 hom., cov: 33)
• Consequence: ENSG00000285330 ENST00000645635.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0940
• Publications: 29 publications found

Genes affected

ENSG00000285330 (HGNC:):

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFI	NM_001375278.1	c.1559-778C>T		intron_variant	Intron 13 of 14		NP_001362207.1
CFI	NM_001440985.1	c.1556-778C>T		intron_variant	Intron 13 of 14		NP_001427914.1
CFI	NM_001375279.1	c.1535-778C>T		intron_variant	Intron 12 of 13		NP_001362208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000285330	ENST00000645635.1	c.1534+6917C>T		intron_variant	Intron 12 of 14			ENSP00000493607.1
CFI	ENST00000695844.1	n.1714-778C>T		intron_variant	Intron 12 of 13
CFI	ENST00000695845.1	n.1713-4232C>T		intron_variant	Intron 12 of 12

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55465 AN: 151978 Hom.: 11269 Cov.: 33

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.480

Gnomad EAS AF: 0.558

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.414

Gnomad OTH AF: 0.399

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

GnomAD4 genome AF: 0.365 AC: 55457 AN: 152096 Hom.: 11265 Cov.: 33 AF XY: 0.372 AC XY: 27664 AN XY: 74342

African (AFR) AF: 0.180 AC: 7477 AN: 41508

American (AMR) AF: 0.462 AC: 7057 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 1666 AN: 3470

East Asian (EAS) AF: 0.558 AC: 2895 AN: 5184

South Asian (SAS) AF: 0.419 AC: 2016 AN: 4816

European-Finnish (FIN) AF: 0.465 AC: 4904 AN: 10538

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.414 AC: 28174 AN: 67978

Other (OTH) AF: 0.395 AC: 836 AN: 2114

Alfa AF: 0.408 Hom.: 39845

Bravo AF: 0.359

Asia WGS AF: 0.447 AC: 1556 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.1
DANN	Benign	0.73
PhyloP100		-0.094

Splicing

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

Other links and lift over

dbSNP: rs7439493; hg19: chr4-110656730;