rs587780563

Positions:

• chrX-153932111-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_003491.4(NAA10):​c.346C>T​(p.Arg116Trp) 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. Variant has been reported in ClinVar as Likely 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:13
• Conservation: PhyloP100: 7.30

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832
• PP5: Variant X-153932111-G-A is Pathogenic according to our data. Variant chrX-153932111-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 139644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153932111-G-A is described in Lovd as [Pathogenic]. Variant chrX-153932111-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAA10	NM_003491.4	c.346C>T	p.Arg116Trp	missense_variant	6/8	ENST00000464845.6	NP_003482.1
NAA10	NM_001256120.2	c.328C>T	p.Arg110Trp	missense_variant	6/8		NP_001243049.1
NAA10	NM_001256119.2	c.341+205C>T		intron_variant			NP_001243048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAA10	ENST00000464845.6	c.346C>T	p.Arg116Trp	missense_variant	6/8	1	NM_003491.4	ENSP00000417763.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ogden syndrome Pathogenic:7

Pathogenic, no assertion criteria provided	research	Laboratory of Medical Genetics, University of Torino	Oct 09, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Mar 31, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 08, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000139644). The variant has been previously reported as de novo in a similarly affected individual (PMID: 27094817). A different missense change at the same codon (p.Arg116Gln) has been reported to be associated with NAA10 related disorder (ClinVar ID: VCV001326724). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Oct 29, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 moderated -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2021	Published functional studies demonstrate a damaging effect; a reduction in the catalytic activity (Popp et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25099252, 23871722, 23020937, 27296530, 27094817, 29957440, 30577886) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

NAA10-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 04, 2023	The NAA10 c.346C>T variant is predicted to result in the amino acid substitution p.Arg116Trp. This variant has been reported in the heterozygous and hemizygous states in patients with intellectual disability, development delay and eyelid myoclonus; in the majority of cases, this variant was found to be de novo (see for example, Rauch et al. 2012. PubMed ID: 23020937; Valentine et al. 2018. PubMed ID: 29957440; Baker et al. 2019. PubMed ID: 30577886). This variant was also confirmed to be de novo in an individual with intellectual disability and microcephaly tested at PreventionGenetics. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare in the general population. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as a de novo change in several individuals with NAA10-related disorder (PMID: 25099252, 29957440). In vitro studies using N-terminal acetylation assays demonstrated protein with this variant had significant reduction in the catalytic activity of the enzyme in comparison to wild type protein (PMID: 25099252). The c.346C>T (p.Arg116Trp) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.346C>T (p.Arg116Trp) variant affects a highly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.346C>T (p.Arg116Trp) variant is classified as a Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.;.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.7	D;D;D;D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.047	D;T;T;.
Polyphen		0.19	B;.;.;.
Vest4		0.68
MutPred		0.53		Loss of disorder (P = 0.0114);Loss of disorder (P = 0.0114);Loss of disorder (P = 0.0114);.;
MVP		0.89
MPC		2.3
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780563; hg19: chrX-153197564; COSMIC: COSV64169392; COSMIC: COSV64169392;