A2ML1

protein-coding

alpha-2-macroglobulin like 1, the group of Alpha-2-macroglobulin family

Gene summary

This gene encodes a member of the alpha-macroglobulin superfamily. The encoded protein is thought to be an N-glycosylated monomeric protein that acts as an inhibitor of several proteases. It has been shown to form covalent interactions with proteases, and has been reported as the p170 antigen recognized by autoantibodies in the autoimmune disease paraneoplastic pemphigus (PNP; PMID:20805888). Mutations in these gene have also been associated with some cases of Noonan syndrome (NS; PMID:24939586) as well as some cases of otitis media (PMID:26121085). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

Previous symbols:

CPAMD9

MANE transcript

NM_144670.6

Inheritance

ClinVar variants

P:2U:999B:509

Top phenotype

Otitis media, susceptibility to

gnomAD constraint

pLI —, LoF o/e 0.77

Max pathogenic AF

—

Genomic locus

chr12:8,822,621-8,887,001

External References & Databases

Ensembl (ENSG00000166535)

Transcript & Mutation Effects

hg38 • Region Span ~64.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Noonan syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: PanelApp Australia

Noonan syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: ClinGen

There have been two studies suggesting that A2ML1 can cause a RASopathy phenotype. Both Vissers et al. 2015 and van Trier et al. 2015 have identified variants in A2ML1 in patients with Noonan syndrome (NS). However, none of these variants could be scored due to their high frequency in the general population, lack of functional impact, or lack of segregation with disease (gnomad.broadinstitute.org, (van Trier et al., 2015; Vissers et al., 2015). As a result, no convincing genetic evidence has been published to associate the A2ML1 gene with RASopathies. However, there is a knock-in zebrafish model that developed cardiac and craniofacial defects similar to those caused by other RASopathy variants (Vissers et al., 2015). The association between A2ML1 and Noonan syndrome remains Disputed. The ClinGen RASopathy Expert Panel found no evidence associating A2ML1 with cardiofaciocutaneous syndrome, Costello syndrome, NS with loose anagen hair or NS with multiple lentigines. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 6/7/18 (SOP Version 5).

Noonan syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Otitis media, susceptibility toAD

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals may have increased susceptibility to otitis media, and awareness may allow awareness leading to prompt diagnosis and treatment of otitis media

Refs: 26121085

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to A2ML1 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 1426

not specifiedTotal: 972

A2ML1-related disorderTotal: 131

Otitis media, susceptibility toTotal: 46

Otitis mediaTotal: 15

Nonsyndromic otitis mediaTotal: 9

Noonan syndromeTotal: 6

Noonan syndrome 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_144670.6. 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			9 clinvar	376 clinvar	4 clinvar	389
missense			861 clinvar	108 clinvar	10 clinvar	979
nonsense		1 clinvar	47 clinvar	4 clinvar		52
start loss						0
frameshift			47 clinvar	4 clinvar	1 clinvar	52
splice donor/acceptor (+/-2bp)		1 clinvar	35 clinvar	2 clinvar		38
Total	0	2	999	494	15	1510

Highest pathogenic variant AF is 0.0000041123776

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_144670.6	RefSeq	NP_653271.3	35	MANE Select
ENST00000299698.12	Ensembl	ENSP00000299698.7	35	MANE Select
NM_001282424.3	RefSeq	NP_001269353.2	24	Standard
ENST00000536789.5	Ensembl	ENSP00000440662.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of endopeptidase activity
regulation of endopeptidase activity

Molecular Function

serine-type endopeptidase inhibitor activity
peptidase inhibitor activity

Cellular Component

extracellular space
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000299698
Coding exons: 35
Length: 64530
Individuals with no LoFs: 112756
Homozygous LoFs: 336
Heterozygous LoFs: 11707
Defined: 124799
p: 0.0495

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.327	766	792	0.967	0.0000414	9472
Missense (PolyPhen)		183	202.78	0.90244		2583
Synonymous	-0.0672	316	314	1.00	0.0000177	2835
Loss of Function	1.91	63	81.6	0.772	0.00000397	960

Population LoF Frequency

Population	CAF	p-value	Status
African	0.069	0.069	notable
Latino/Admixed American	0.033	0.033	notable
Ashkenazi Jewish	0.066	0.067	notable
East Asian	0.0049	0.0049	notable
Finnish	0.033	0.033	notable
European (Non-Finnish)	0.055	0.055	notable
South Asian	0.070	0.069	notable
Other	0.057	0.057	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Is able to inhibit all four classes of proteinases by a unique 'trapping' mechanism. This protein has a peptide stretch, called the 'bait region' which contains specific cleavage sites for different proteinases. When a proteinase cleaves the bait region, a conformational change is induced in the protein which traps the proteinase. The entrapped enzyme remains active against low molecular weight substrates (activity against high molecular weight substrates is greatly reduced). Following cleavage in the bait region a thioester bond is hydrolyzed and mediates the covalent binding of the protein to the proteinase (By similarity). Displays inhibitory activity against chymotrypsin, papain, thermolysin, subtilisin A and, to a lesser extent, elastase but not trypsin. May play an important role during desquamation by inhibiting extracellular proteases. {ECO:0000250|UniProtKB:P01023, ECO:0000269|PubMed:16298998}.;

Recessive Scores

pRec: 0.0833

Intolerance Scores

LoFtool: 0.960
RVIS EVS: 2.42
RVIS percentile EVS: 98.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.155

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High