AMFR

protein-coding

autocrine motility factor receptor, the group of Ring finger proteins

Gene summary

This locus encodes a glycosylated transmembrane receptor. Its ligand, autocrine motility factor, is a tumor motility-stimulating protein secreted by tumor cells. The encoded receptor is also a member of the E3 ubiquitin ligase family of proteins. It catalyzes ubiquitination and endoplasmic reticulum-associated degradation of specific proteins. [provided by RefSeq, Feb 2012]

MANE transcript

NM_001144.6

Inheritance

ClinVar variants

P:7U:85B:7

Top phenotype

Spastic paraplegia 89, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr16:56,361,452-56,425,545

External References & Databases

Ensembl (ENSG00000159461)

Transcript & Mutation Effects

hg38 • Region Span ~64.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spastic paraplegia 89, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0957274

Submitter: PanelApp Australia

spastic paraplegia 89, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0957274

Submitter: Labcorp Genetics (formerly Invitae)

spastic paraplegia 89, autosomal recessiveMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0957274

Submitter: G2P

Clinical Genomic Database (CGD)

Spastic paraplegia 89, autosomal recessiveAR

Manifestation: Neurologic

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: 37119330

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AMFR variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 74

not providedTotal: 9

Spastic paraplegia 89, autosomal recessiveTotal: 7

Marfanoid habitus and intellectual disabilityTotal: 1

Breast ductal adenocarcinomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001144.6. 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			1 clinvar	5 clinvar		6
missense			79 clinvar	2 clinvar		81
nonsense	3 clinvar		1 clinvar			4
start loss						0
frameshift	2 clinvar					2
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	4 clinvar			6
Total	6	1	85	7	0	99

Highest pathogenic variant AF is 0.0000065758327

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001144.6	RefSeq	NP_001135.3	14	MANE Select
ENST00000290649.10	Ensembl	ENSP00000290649.5	14	MANE Select
NM_001323511.2	RefSeq	NP_001310440.1	13	Standard
NM_001323512.2	RefSeq	NP_001310441.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein processing in endoplasmic reticulum - Homo sapiens (human)
Sterol Regulatory Element-Binding Proteins (SREBP) signalling
ER Quality Control Compartment (ERQC)
Calnexin/calreticulin cycle
Post-translational protein modification

Biological Process

protein polyubiquitination
protein folding
ubiquitin-dependent protein catabolic process
signal transduction
aging

Molecular Function

ubiquitin-protein transferase activity
protein binding
protein binding, bridging
ubiquitin-ubiquitin ligase activity
signaling receptor activity

Cellular Component

nucleus
endoplasmic reticulum
endoplasmic reticulum membrane
Golgi apparatus
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000290649
Coding exons: 14
Length: 64087
Individuals with no LoFs: 125711
Homozygous LoFs: 0
Heterozygous LoFs: 37
Defined: 125748
p: 0.000147

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.87	267	368	0.726	0.0000229	4205
Missense (PolyPhen)		50	87.182	0.57351		881
Synonymous	1.30	118	137	0.859	0.00000894	1284
Loss of Function	3.20	13	32.8	0.396	0.00000183	354

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.00083	0.00083	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000037	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase that mediates the polyubiquitination of a number of proteins such as CD3D, CYP3A4, CFTR and APOB for proteasomal degradation. Component of a VCP/p97- AMFR/gp78 complex that participates in the final step of endoplasmic reticulum-associated degradation (ERAD). The VCP/p97- AMFR/gp78 complex is involved in the sterol-accelerated ERAD degradation of HMGCR through binding to the HMGCR-INSIG complex at the ER membrane and initiating ubiquitination of HMGCR. The ubiquitinated HMGCR is then released from the ER by the complex into the cytosol for subsequent destruction. Also regulates ERAD through the ubiquitination of UBL4A a component of the BAG6/BAT3 complex. Also acts as a scaffold protein to assemble a complex that couples ubiquitination, retranslocation and deglycosylation. Mediates tumor invasion and metastasis as a receptor for the GPI/autocrine motility factor. {ECO:0000269|PubMed:10456327, ECO:0000269|PubMed:11724934, ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:19103148, ECO:0000269|PubMed:24424410}.;

Recessive Scores

pRec: 0.172

Intolerance Scores

LoFtool: 0.602
RVIS EVS: -1.09
RVIS percentile EVS: 7.05

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.876

Gene Damage Prediction

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