CFHR5

protein-coding

complement factor H related 5, the group of Sushi domain containing|Complement system regulators and receptors

Gene summary

This gene is a member of a small complement factor H (CFH) gene cluster on chromosome 1. Each member of this gene family contains multiple short consensus repeats (SCRs) typical of regulators of complement activation. The protein encoded by this gene has nine SCRs with the first two repeats having heparin binding properties, a region within repeats 5-7 having heparin binding and C reactive protein binding properties, and the C-terminal repeats being similar to a complement component 3 b (C3b) binding domain. This protein co-localizes with C3, binds C3b in a dose-dependent manner, and is recruited to tissues damaged by C-reactive protein. Allelic variations in this gene have been associated, but not causally linked, with two different forms of kidney disease: membranoproliferative glomerulonephritis type II (MPGNII) and hemolytic uraemic syndrome (HUS). [provided by RefSeq, Jan 2010]

Previous symbols:

CFHL5

MANE transcript

NM_030787.4

Inheritance

ClinVar variants

P:4U:220B:90

Top phenotype

CFHR5 deficiency

gnomAD constraint

pLI —, LoF o/e 1.44

Max pathogenic AF

—

Genomic locus

chr1:196,975,010-197,009,678

External References & Databases

Ensembl (ENSG00000134389)

Transcript & Mutation Effects

hg38 • Region Span ~34.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

C3 glomerulonephritisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013892

Submitter: Labcorp Genetics (formerly Invitae)

C3 glomerulonephritisMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013892

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

CFHR5 deficiencyAD

Manifestation: Renal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 20800271; 22503529

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CFHR5 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 183

C3 glomerulonephritisTotal: 111

Inborn genetic diseasesTotal: 98

not specifiedTotal: 57

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type IITotal: 49

CFHR5 deficiencyTotal: 49

Atypical hemolytic-uremic syndromeTotal: 13

Kidney disorderTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_030787.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	37 clinvar	1 clinvar	45
missense			174 clinvar	49 clinvar	1 clinvar	224
nonsense		2 clinvar	15 clinvar	1 clinvar		18
start loss			1 clinvar			1
frameshift		2 clinvar	19 clinvar			21
splice donor/acceptor (+/-2bp)			4 clinvar	1 clinvar		5
Total	0	4	220	88	2	314

Highest pathogenic variant AF is 0.0000310016

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_030787.4	RefSeq	NP_110414.1	10	MANE Select
ENST00000256785.5	Ensembl	ENSP00000256785.4	10	MANE Select
ENST00000699466.1	Ensembl	ENSP00000514393.1	8	Standard
ENST00000699466.2	Ensembl	ENSP00000514393.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Innate Immune System
Immune System
Regulation of Complement cascade
Complement cascade

Biological Process

complement activation, alternative pathway
regulation of complement activation
negative regulation of protein binding
positive regulation of cytolysis

Molecular Function

protein binding
protein homodimerization activity
protein heterodimerization activity

Cellular Component

extracellular region
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000256785
Coding exons: 10
Length: 32138
Individuals with no LoFs: 125379
Homozygous LoFs: 0
Heterozygous LoFs: 364
Defined: 125743
p: 0.00145

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.903	349	305	1.15	0.0000150	3702
Missense (PolyPhen)		115	108.61	1.0589		1281
Synonymous	-1.91	130	105	1.24	0.00000542	1046
Loss of Function	-2.16	41	28.5	1.44	0.00000140	361

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00074	0.00074	rare
Latino/Admixed American	0.00075	0.00075	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00033	0.00033	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.0095	0.0095	notable
Other	0.0021	0.0021	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in complement regulation. The dimerized forms have avidity for tissue-bound complement fragments and efficiently compete with the physiological complement inhibitor CFH. {ECO:0000269|PubMed:23487775}.;
Disease: DISEASE: CFHR5 deficiency (CFHR5D) [MIM:614809]: A progressive disease characterized by glomerulonephritis, hematuria, renal failure, end-stage renal disease, subendothelial and mesangial glomerular C3 deposits, mesangial matrix expansion, increased glomerular cellularity, and segmental capillary wall thickening. Hematuria may become apparent after respiratory infections. {ECO:0000269|PubMed:20800271, ECO:0000269|PubMed:22503529}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.613
RVIS EVS: 0.18
RVIS percentile EVS: 66.24

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.588

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium