chrX-153932073-A-C

Position:

• chrX-153932073-A-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_003491.4(NAA10):​c.384T>G​(p.Phe128Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: NAA10 NM_003491.4 missense, splice_region
• Scores: Splicing: ADA: 0.0002552
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.33

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]

NAA10 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant X-153932073-A-C is Pathogenic according to our data. Variant chrX-153932073-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 280237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153932073-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAA10	NM_003491.4	c.384T>G	p.Phe128Leu	missense_variant, splice_region_variant	6/8	ENST00000464845.6	NP_003482.1
NAA10	NM_001256120.2	c.366T>G	p.Phe122Leu	missense_variant, splice_region_variant	6/8		NP_001243049.1
NAA10	NM_001256119.2	c.341+243T>G		intron_variant			NP_001243048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAA10	ENST00000464845.6	c.384T>G	p.Phe128Leu	missense_variant, splice_region_variant	6/8	1	NM_003491.4	ENSP00000417763.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ogden syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	Jan 06, 2017	Intellectual disability, severe; extrapyramIntellectual disabilityal syndrome; microcephaly; late onset epilepsy; precocious puberty -
Pathogenic, criteria provided, single submitter	clinical testing	Arnesen Lab, University of Bergen	-	Published functional studies for a NAA10 F128L missense variant, caused by a different nucleotide substitution (c.384T>A), demonstrated reduced catalytic activity (Saunier et al., 2016) and the variant was reported as pathogenic. The NAA10 c.384T>G result in the same F128L missense variant and is therefore also considered pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 17, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2023	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31127942, 31036916, 35039925, 28708303) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.;.;T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	3.2	M;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.1	D;D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;.
Polyphen		0.45	P;.;.;.
Vest4		0.92
MutPred		0.81		Loss of catalytic residue at F128 (P = 0.0648);Loss of catalytic residue at F128 (P = 0.0648);Loss of catalytic residue at F128 (P = 0.0648);.;
MVP		0.99
MPC		2.4
ClinPred		0.98	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00026
dbscSNV1_RF	Benign	0.21
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

Publications

LitVar

Other links and lift over

dbSNP: rs878853263; hg19: chrX-153197526;