A2ML1

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

Basic information

Region (hg38): 12:8822620-8887001

Previous symbols: [ "CPAMD9" ]

Links

ENSG00000166535 ∙ NCBI:144568 ∙ OMIM:610627 ∙ HGNC:23336 ∙ Uniprot:A8K2U0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Noonan syndrome (Supportive), mode of inheritance: AD
• Noonan syndrome (Disputed Evidence), mode of inheritance: AD
• Noonan syndrome (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Otitis media, susceptibility to	AD	Allergy/Immunology/Infectious	Individuals may have increased susceptibility to otitis media, and awareness may allow awareness leading to prompt diagnosis and treatment of otitis media	Allergy/Immunology/Infectious	26121085

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the A2ML1 gene.

• not provided (1150 variants)
• Inborn genetic diseases (425 variants)
• not specified (266 variants)
• Otitis media, susceptibility to (40 variants)
• A2ML1-related condition (16 variants)
• Otitis media (16 variants)
• Nonsyndromic otitis media (4 variants)
• Noonan syndrome (2 variants)
• Noonan syndrome 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the A2ML1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			7	247	10	264
missense			527	35	17	579
nonsense		1	36	1		38
start loss						0
frameshift			28	1	2	31
inframe indel			8			8
splice donor/acceptor (+/-2bp)			23		1	24
splice region			28	32	5	65
non coding			14	148	157	319
Total	0	1	643	432	187

Variants in A2ML1

This is a list of pathogenic ClinVar variants found in the A2ML1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-8822636-T-C		not specified	Likely benign (Jan 16, 2018)
12-8822660-T-A		not specified • Otitis media, susceptibility to	Benign/Likely benign (Jan 20, 2024)
12-8822661-C-T		Otitis media, susceptibility to • Otitis media	Likely pathogenic (Oct 30, 2018)
12-8822664-C-G			Uncertain significance (Nov 10, 2020)
12-8822672-A-G		not specified	Benign/Likely benign (Jul 09, 2023)
12-8822677-T-C		not specified	Uncertain significance (Dec 24, 2021)
12-8822680-T-A		not specified	Uncertain significance (Sep 23, 2021)
12-8822687-A-G			Likely benign (Feb 12, 2020)
12-8822695-C-A		not specified	Uncertain significance (Mar 23, 2020)
12-8822701-C-A			Uncertain significance (Oct 16, 2020)
12-8822701-CAGA-C			Uncertain significance (Jul 10, 2022)
12-8822703-G-A		not specified	Uncertain significance (May 15, 2023)
12-8822706-G-A		not specified	Likely benign (Nov 02, 2022)
12-8822712-C-A			Uncertain significance (Dec 24, 2021)
12-8822712-C-G		not specified	Conflicting classifications of pathogenicity (Jan 22, 2024)
12-8822713-C-T		not specified	Uncertain significance (Dec 16, 2019)
12-8822714-G-A			Uncertain significance (Apr 19, 2023)
12-8822714-G-C			Uncertain significance (Dec 11, 2019)
12-8822722-T-C			Likely benign (Aug 24, 2023)
12-8823009-A-G			Benign (Jun 19, 2018)
12-8823168-T-G			Likely benign (Nov 15, 2021)
12-8823173-CT-C		not specified	Conflicting classifications of pathogenicity (Mar 01, 2022)
12-8823178-A-G		not specified • A2ML1-related disorder	Benign/Likely benign (Nov 22, 2023)
12-8823186-T-TA			Uncertain significance (Jan 29, 2024)
12-8823187-A-G		not specified	Conflicting classifications of pathogenicity (Sep 18, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
A2ML1	protein_coding	protein_coding	ENST00000299698	35	64530

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.61e-34	0.0208	112756	336	11707	124799	0.0495

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.327	766	792	0.967	0.0000414	9472
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.102	0.102
Ashkenazi Jewish	0.0663	0.0666
East Asian	0.00490	0.00491
Finnish	0.0334	0.0332
European (Non-Finnish)	0.0555	0.0552
Middle Eastern	0.00490	0.00491
South Asian	0.0700	0.0693
Other	0.0568	0.0572

dbNSFP

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

Haploinsufficiency Scores

• pHI: 0.0600
• hipred: N
• hipred_score: 0.145
• ghis: 0.382

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.155

Gene Damage Prediction

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

Gene ontology

• Biological process: negative regulation of endopeptidase activity;regulation of endopeptidase activity
• Cellular component: extracellular space;extracellular exosome
• Molecular function: serine-type endopeptidase inhibitor activity;peptidase inhibitor activity