NAA15

protein-coding

N-alpha-acetyltransferase 15, NatA auxiliary subunit, the group of N-alpha-acetyltransferase subunits|Armadillo like helical domain containing

Gene summary

N-alpha-acetylation is among the most common post-translational protein modifications in eukaryotic cells. This process involves the transfer of an acetyl group from acetyl-coenzyme A to the alpha-amino group on a nascent polypeptide and is essential for normal cell function. This gene encodes the auxillary subunit of the N-terminal acetyltransferase A (NatA) complex. [provided by RefSeq, Jan 2017]

Previous symbols:

NARG1

MANE transcript

NM_057175.5

Inheritance

ClinVar variants

P:183U:311B:97

Top phenotype

Intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalities

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chr4:139,301,446-139,420,033

External References & Databases

Ensembl (ENSG00000164134)

Transcript & Mutation Effects

hg38 • Region Span ~118.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030916

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0030916

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030916

Submitter: G2P

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

Variants in *NAA15* were first reported in individuals with intellectual disability and autism by Stessman et al. in 2017 (PMID: 28191889), in a case cohort study of neurodevelopmental disorders in which 13 individuals with *NAA15* variants were described. Two additional case series have subsequently been published (PMIDs: 29656860, 31127942), with over 40 probands in total described in the literature. Affected individuals typically harbor *de novo* heterozygous truncating variants, although milder cases with missense variants and inheritance in families have been documented. Phenotypic features include variable levels of intellectual disability, motor and speech delay, and autism spectrum disorder. Some individuals also present with dysmorphic features, cardiac abnormalities, and seizures. *NAA15* encodes the enzyme N-alpha-Acetyltransferase 15, a subunit of the NatA complex involved in co-translational acetylation of the peptide N-terminus. This gene-disease relationship is also supported by experimental evidence, including protein interaction with NAA10, involved in a neurodevelopmental disorder, and functional alterations in non-patient cells (PMIDs: 29656860, 33557580). In summary, there is definitive evidence supporting the relationship between *NAA15* and autosomal dominant syndromic intellectual disability. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on January 5, 2022 (SOP Version 8).

intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030916

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030916

Submitter: Illumina

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalitiesAD

Manifestation: Craniofacial; Musculoskeletal; 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: 28191889; 31127942

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NAA15 variants in ClinVar

17 Conditions Cataloged

not providedTotal: 462

Intellectual disability, autosomal dominant 50Total: 137

Inborn genetic diseasesTotal: 99

NAA15-related disorderTotal: 45

not specifiedTotal: 37

See casesTotal: 8

Intellectual disabilityTotal: 6

Neurodevelopmental disorderTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_057175.5. 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	6 clinvar	74 clinvar	7 clinvar	88
missense	3 clinvar	17 clinvar	283 clinvar	16 clinvar		319
nonsense	35 clinvar	24 clinvar	4 clinvar			63
start loss						0
frameshift	38 clinvar	32 clinvar	3 clinvar			73
splice donor/acceptor (+/-2bp)	15 clinvar	18 clinvar	15 clinvar			48
Total	91	92	311	90	7	591

Highest pathogenic variant AF is 0.000008367104

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_057175.5	RefSeq	NP_476516.1	20	MANE Select
ENST00000296543.10	Ensembl	ENSP00000296543.4	20	MANE Select
NM_001410842.1	RefSeq	NP_001397771.1	20	Standard
ENST00000398947.1	Ensembl	ENSP00000381920.1	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase

Biological Process

angiogenesis
N-terminal protein amino acid acetylation
N-terminal peptidyl-methionine acetylation
cell differentiation
negative regulation of apoptotic process

Molecular Function

RNA binding
peptide alpha-N-acetyltransferase activity
protein binding
acetyltransferase activity
ribosome binding

Cellular Component

nucleus
transcription factor complex
cytoplasm
cytosol
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000296543
Coding exons: 20
Length: 118579
Individuals with no LoFs: 124766
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 124779
p: 0.0000521

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.81	202	422	0.478	0.0000201	5720
Missense (PolyPhen)		51	164.36	0.3103		2209
Synonymous	0.686	136	147	0.928	0.00000713	1460
Loss of Function	5.41	7	47.0	0.149	0.00000220	686

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000063	0.000058	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000056	0.000056	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.000036	0.000033	rare
Other	0.00017	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Auxillary subunit of the N-terminal acetyltransferase A (NatA) complex which displays alpha (N-terminal) acetyltransferase activity. The NAT activity may be important for vascular, hematopoietic and neuronal growth and development. Required to control retinal neovascularization in adult ocular endothelial cells. In complex with XRCC6 and XRCC5 (Ku80), up-regulates transcription from the osteocalcin promoter. {ECO:0000269|PubMed:11687548, ECO:0000269|PubMed:12145306, ECO:0000269|PubMed:15496142}.;
Disease: DISEASE: Mental retardation, autosomal dominant 50 (MRD50) [MIM:617787]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:28191889}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.198

Intolerance Scores

LoFtool: 0.438
RVIS EVS: -0.89
RVIS percentile EVS: 10.3

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
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