CFHR4

protein-coding

complement factor H related 4, the group of Complement system regulators and receptors|Sushi domain containing

Gene summary

This gene is a member of the complement factor H (CFH) gene family, and encodes one of the 5 CFH-related (CFHR) proteins. These 5 genes are closely linked to the CFH gene on chromosome 1q31-q32. The CFHRs are secreted plasma proteins synthesized primarily by the hepatocytes, and composed of highly-related short consensus repeats (SCRs). This protein enhances the cofactor activity of CFH, and is involved in complement regulation. It can associate with lipoproteins and may play a role in lipid metabolism. Alternatively spliced transcript variants encoding different isoforms (varying in the number of SCRs) have been described for this gene. [provided by RefSeq, Jan 2011]

Previous symbols:

CFHL4

MANE transcript

NM_001201550.3

Inheritance

AD, AR, Digenic

ClinVar variants

U:112B:71

Top phenotype

Hemolytic-uremic syndrome, atypical, susceptibility to

gnomAD constraint

pLI —, LoF o/e 0.95

Max pathogenic AF

—

Genomic locus

chr1:196,888,014-196,918,795

External References & Databases

Ensembl (ENSG00000134365)

Transcript & Mutation Effects

hg38 • Region Span ~30.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

Clinical Genomic Database (CGD)

Hemolytic-uremic syndrome, atypical, susceptibility toAD/AR/Digenic

Manifestation: Hematologic; Renal

Intervention: Hematologic; Pharmacogenomic; Renal

Rationale: In Hemolytic-uremic syndrome, the choice of specific treatment modalities (eg, danazol, plasma exchange, plasma therapy), as well as decision to perform renal transplant, may be dictated by genetic diagnosis, and certain agents/precipitating factors should be avoided (eg, certain medications)

Comments: Deletions related to hemolytic-uremic syndrome involve a contiguous deletion with CFHR3 or CFHR4

Refs: 19861685; 20301541

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CFHR4 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 162

not providedTotal: 72

Atypical hemolytic-uremic syndromeTotal: 2

Kidney disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001201550.3. 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				23 clinvar	1 clinvar	24
missense			108 clinvar	41 clinvar	2 clinvar	151
nonsense			2 clinvar	2 clinvar		4
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar	1 clinvar	1 clinvar	3
Total	0	0	112	67	4	183

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001201550.3	RefSeq	NP_001188479.1	10	MANE Select
ENST00000608469.6	Ensembl	ENSP00000477162.2	10	MANE Select
NM_001201551.2	RefSeq	NP_001188480.1	10	Standard
NM_006684.5	RefSeq	NP_006675.2	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Human Complement System
Innate Immune System
Immune System
Regulation of Complement cascade
Complement cascade

Biological Process

lipid transport
regulation of complement activation

Molecular Function

lipid transporter activity

Cellular Component

extracellular region

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367416
Coding exons: 10
Length: 68732
Individuals with no LoFs: 125250
Homozygous LoFs: 6
Heterozygous LoFs: 485
Defined: 125741
p: 0.00195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.17	357	300	1.19	0.0000143	3730
Missense (PolyPhen)		113	97.267	1.1618		1171
Synonymous	-2.25	138	108	1.28	0.00000552	1030
Loss of Function	0.265	28	29.6	0.947	0.00000134	389

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00096	0.00092	rare
Latino/Admixed American	0.00039	0.00038	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0052	0.0052	notable
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00032	0.00031	rare
South Asian	0.012	0.011	notable
Other	0.0014	0.0013	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in complement regulation. Can associate with lipoproteins and may play a role in lipid metabolism.;

Recessive Scores

pRec: 0.135

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

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