rs878853264

Variant names:

• chrX-153932075-A-T
• rs878853264
• NM_003491.4:c.382T>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_003491.4(NAA10):​c.382T>A​(p.Phe128Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F128L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: NAA10 NM_003491.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.53
• Publications: 14 publications found

Genes affected

NAA10 (HGNC:18704): (N-alpha-acetyltransferase 10, NatA catalytic subunit) 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 an N-terminal acetyltransferase that functions as the catalytic subunit of the major amino-terminal acetyltransferase A complex. Mutations in this gene are the cause of Ogden syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

ARHGAP4 (HGNC:674): (Rho GTPase activating protein 4) This gene encodes a member of the rhoGAP family of proteins which play a role in the regulation of small GTP-binding proteins belonging to the RAS superfamily. The protein encoded by the orthologous gene in rat is localized to the Golgi complex and can redistribute to microtubules. The rat protein stimulates the activity of some Rho GTPases in vitro. Genomic deletions of this gene and a neighboring gene have been found in patients with nephrogenic diabetes insipidus. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ARHGAP4 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-153932073-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 280237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 26 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 2.408 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to NAA10-related syndrome, Ogden syndrome, microphthalmia, Lenz type, microphthalmia, syndromic 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant X-153932075-A-T is Pathogenic according to our data. Variant chrX-153932075-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 236259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003491.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAA10	NM_003491.4	MANE Select	c.382T>A	p.Phe128Ile	missense	Exon 6 of 8	NP_003482.1
	NAA10	NM_001256120.2		c.364T>A	p.Phe122Ile	missense	Exon 6 of 8	NP_001243049.1
	NAA10	NM_001256119.2		c.341+241T>A		intron	N/A	NP_001243048.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAA10	ENST00000464845.6	TSL:1 MANE Select	c.382T>A	p.Phe128Ile	missense	Exon 6 of 8	ENSP00000417763.1
	NAA10	ENST00000466877.5	TSL:1	n.693T>A		non_coding_transcript_exon	Exon 5 of 7
	NAA10	ENST00000370009.5	TSL:1	c.341+241T>A		intron	N/A	ENSP00000359026.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ogden syndrome Pathogenic:2

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team

Mar 31, 2016

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NAA10-related syndrome Pathogenic:1

May 14, 2025

Clinical Genomic Analysis (GENYSIS) Core, University of North Carolina at Chapel Hill

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

NAA10 c.382T>A, p.(Phe128Ile), is a missense variant in exon 6 of 8 that changes a single highly conserved amino acid from a phenylalanine to an isoleucine in the encoded protein. This variant is absent from control individuals in the gnomADv4.1 population database, is predicted by in silico models to have a damaging effect on the protein, and has been reported as pathogenic/likely pathogenic in ClinVar. The c.382T>A variant has been seen in at least one other affected female with microcephaly, eye abnormalities, congenital blindness, delayed speech and language, hypoplasia of the corpus callosum, thoracic kyphosis, limb hypertonia, axial hypotonia, EEG with generalized slow activity, and dyskinesia (PMIDs 26757139, 39825153, 29095811). In addition, variants that result in a different amino acid change, p.Phe128Leu, have been reported as pathogenic in ClinVar and shown to result in significantly reduced NAA10 catalytic activity, supporting Phe128 as a critical amino acid (PMID: 27094817). Based on the available information, we consider the NAA10 c.382T>A, p.(Phe128Ile), variant to be likely pathogenic. ACMG codes: PS2 (confirmed de novo), PM2_Supporting (absent from gnomAD), PM5 (p.Phe128Leu is also pathogenic), PP3_Moderate (REVEL score between 0.773 and 0.932).

Intellectual disability Pathogenic:1

Jan 01, 2014

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		8.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.95	P
Vest4		0.91
MutPred		0.79		Loss of loop (P = 0.0374)
MVP		0.99
MPC		4.0
ClinPred		1.0	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs878853264; hg19: chrX-153197528;