ANG

protein-coding

angiogenin, the group of Ribonuclease A family|Endoribonucleases

Gene summary

The protein encoded by this gene is a member of the RNase A superfamily though it has relatively weak ribonucleolytic activity. This protein is a potent mediator of new blood vessel formation and thus, in addition to the name RNase5, is commonly called angiogenin. This protein induces angiogenesis after binding to actin on the surface of endothelial cells. This protein also accumulates at the nucleolus where it stimulates ribosomal transcription. Under stress conditions this protein translocates to the cytosol where it hydrolyzes cellular tRNAs and influences protein synthesis. A signal peptide is cleaved from the precursor protein to produce a mature protein which contains a nuclear localization signal, a cell binding motif, and a catalytic domain. This protein has been shown to be both neurotrophic and neuroprotective and the mature protein has antimicrobial activity against some bacteria and fungi, including S. pneumoniae and C. albicans. Due to its effect on rRNA production and angiogenesis this gene plays important roles in cell growth and tumor progression. Mutations in this gene are associated with progression of amyotrophic lateral sclerosis (ALS). This gene and the neighboring RNase4 gene share promoters and 5' exons though each gene then splices to a distinct 3' exon containing the complete coding region of each gene. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2020]

MANE transcript

NM_001097577.3

Inheritance

ClinVar variants

P:8U:58B:26

Top phenotype

Amyotrophic lateral sclerosis 9

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr14:20,684,177-20,698,971

External References & Databases

Ensembl (ENSG00000214274)

Transcript & Mutation Effects

hg38 • Region Span ~14.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

amyotrophic lateral sclerosis type 9DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012753

Submitter: Ambry Genetics

amyotrophic lateral sclerosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: Orphanet

amyotrophic lateral sclerosis type 9STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012753

Submitter: Labcorp Genetics (formerly Invitae)

amyotrophic lateral sclerosis type 9LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012753

Submitter: ClinGen

Pending. ANG was first reported in relation to autosomal dominant amyotrophic lateral sclerosis in 2004 (Greenway et al., PMID 15557516). At least 31 unique missense variants have been reported in humans, of these 16 were eligible for scoring using a minor allele frequency threshold of <0.000005 in the gnomAD v2.1.1 non-neurological conditions dataset. Evidence supporting this gene-disease relationship consists mostly of individual case reports with evidence of angiogenin expression in spinal motor neurons making up the experimental data. Summary of Case Level Data: 2.7 POINTS Variants in this gene have been reported in at least 70 probands in 21 publications (PMIDs 15557516, 16501576, 17886298, 17703939, 18087731, 18852347, 19153377, 19363631, 20577002, 21621297, 22190368, 22292798, 22292843, 22645277, 22752089, 23155438, 23228179, 28160950, 28444446, 31025543, 31432357) of which 23 probands from 6 studies (PMIDs 15557516, 16501576, 17886298, 18087731, 22190368, 22292843) contribute to the case level data score due to many of the most highly reported variants also being present at high frequencies in control datasets and gnomAD v2.1.1 non-neuro. Common functional assays demonstrating the effect of variants on the gene product included nuclear translocation, ribonuclease activity, angiogenic activity and morphology of cultured motor neurons co-cultured with angiogenin with ALS associated variants (PMIDs 17916583, 17886298, 23047679, 22292843, 31025543, 31432357). These assays were not used to increase case-level evidence as functional changes were observed in benign variants for example K41I [K17I]. Evidence of disruption to stress granule formation of variant K64I [K40I] was the only eligible functional data to increase the score of a case-level variant report (PMID 23047679). Summary of Experimental Data: 0.5 POINTS Angiogenin is expressed in fetal and adult spinal motor neurons and endothelial cells (PMID 17886298). A phenotype rescue study was performed on SOD1 G93D mice. In this experiment it was shown that delivery of recombinant angiogenin ameliorated motor symptoms and extended lifespan. However, the phenotype was not fully rescued, and it was not clear what cellular process caused the underlying the results, so this evidence did not contribute towards the overall score (PMID 19109488). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.

amyotrophic lateral sclerosis type 9STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012753

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Amyotrophic lateral sclerosis 9AD

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: 15557516; 16501576; 17886298; 18087731; 18852347; 19153377; 20577002

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ANG variants in ClinVar

8 Conditions Cataloged

not providedTotal: 69

Amyotrophic lateral sclerosis type 9Total: 24

Inborn genetic diseasesTotal: 19

ANG-related disorderTotal: 12

not specifiedTotal: 8

Frontotemporal dementiaTotal: 1

Amyotrophic lateral sclerosisTotal: 1

Amyotrophic lateral sclerosis type 10Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001097577.3. 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				19 clinvar		19
missense	6 clinvar	2 clinvar	53 clinvar	5 clinvar	2 clinvar	68
nonsense			1 clinvar			1
start loss			1 clinvar			1
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)						0
Total	6	2	58	24	2	92

Highest pathogenic variant AF is 0.000017967024

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001097577.3	RefSeq	NP_001091046.1	1	MANE Select
ENST00000397990.5	Ensembl	ENSP00000381077.4	1	MANE Select
NM_001145.4	RefSeq	NP_001136.1	1	Standard
NM_001385271.1	RefSeq	NP_001372200.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cell-cell junction organization
Adherens junctions interactions
Cell junction organization
Cell-Cell communication

Biological Process

angiogenesis
ovarian follicle development
oocyte maturation
response to hypoxia
placenta development

Molecular Function

DNA binding
actin binding
endonuclease activity
ribonuclease activity
signaling receptor binding

Cellular Component

extracellular region
basement membrane
extracellular space
nucleus
nucleolus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000336811
Coding exons: 1
Length: 14795
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0777	83	85.0	0.976	0.00000536	952
Missense (PolyPhen)		22	26.47	0.83113		322
Synonymous	0.324	32	34.4	0.930	0.00000207	306
Loss of Function	0.239	0	0.0668	0.00	2.76e-9	3

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds to actin on the surface of endothelial cells; once bound, angiogenin is endocytosed and translocated to the nucleus. Stimulates ribosomal RNA synthesis including that containing the initiation site sequences of 45S rRNA. Cleaves tRNA within anticodon loops to produce tRNA-derived stress-induced fragments (tiRNAs) which inhibit protein synthesis and triggers the assembly of stress granules (SGs). Angiogenin induces vascularization of normal and malignant tissues. Angiogenic activity is regulated by interaction with RNH1 in vivo. {ECO:0000269|PubMed:12051708, ECO:0000269|PubMed:1400510, ECO:0000269|PubMed:19354288, ECO:0000269|PubMed:21855800}.;
Disease: DISEASE: Amyotrophic lateral sclerosis 9 (ALS9) [MIM:611895]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5- 10% of the cases. {ECO:0000269|PubMed:15557516, ECO:0000269|PubMed:16501576, ECO:0000269|PubMed:17703939, ECO:0000269|PubMed:17886298, ECO:0000269|PubMed:17900154, ECO:0000269|PubMed:18087731, ECO:0000269|PubMed:22292843, ECO:0000269|PubMed:25372031}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Intolerance Scores

RVIS EVS: 0.24
RVIS percentile EVS: 68.98

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.998

Gene Damage Prediction

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