ENST00000645635.1:c.1534+4580A>G

Variant names:

• chr4-109737911-T-C
• rs10033900
• ENST00000645635.1:c.1534+4580A>G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The ENST00000645635.1(ENSG00000285330):c.1534+4580A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. Note: ENST00000645635.1 is not a MANE Select or MANE Plus Clinical transcript for ENSG00000285330; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.535 (AC=81,232) in the gnomAD database across 151,972 control chromosomes, including 21,995 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.61. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.53 (21995 hom., cov: 31)
• Consequence: ENSG00000285330 ENST00000645635.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.63
• Publications: 131 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: Orphanet, Labcorp Genetics (formerly Invitae)
• C3 glomerulonephritis

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); No splicing predictor data available.; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.6099 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000645635.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFI	NM_001375278.1		c.1559-3115A>G		intron	N/A	NP_001362207.1
	CFI	NM_001440985.1		c.1556-3115A>G		intron	N/A	NP_001427914.1
	CFI	NM_001375279.1		c.1535-3115A>G		intron	N/A	NP_001362208.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000285330	ENST00000645635.1		c.1534+4580A>G		intron	N/A	ENSP00000493607.1	A0A2R8Y3M9
	CFI	ENST00000695844.1		n.1714-3115A>G		intron	N/A
	CFI	ENST00000695845.1		n.1712+4580A>G		intron	N/A

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.535	AC:81185	Hom:21986	AN:151852	Cov:31
GnomAD4 genome	AF: 0.535	AC:81232	Hom:21995	AN:151972	Cov:31
TOPMed (Bravo)	AF: 0.547	AC:144803	Hom:40091	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.522	AC:345496	Hom:91008	AN:661396	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.582	AC:1364	Hom:389	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.366	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.490	AC:147	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.335	AC:1170	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.321	AC:2323	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.540	AC:95	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.377	AC:46310	Hom:8821	AN:122712	Cov:
Turkish Variome	AF: 0.527	AC:815	Hom:218	AN:1546	Cov:
UK10K	AF: 0.518	AC:3914	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.377	AC:3380	Hom:637	AN:8960	Cov:

Showing 14 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	2.3
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.8
DANN	Benign	0.72
GPN-Star LLR	N/A	0.36
GPN-Star score	N/A	-0.36
PhyloP100	Benign	1.6

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0

Showing 1 of 1 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10033900;

hg19: chr4-110659067;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar