NM_003491.4(NAA10):c.346C>T (p.Arg116Trp) AND Ogden syndrome

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Feb 23, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000128609.11

Allele description [Variation Report for NM_003491.4(NAA10):c.346C>T (p.Arg116Trp)]

NM_003491.4(NAA10):c.346C>T (p.Arg116Trp)

Gene:

NAA10:N-alpha-acetyltransferase 10, NatA catalytic subunit [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_003491.4(NAA10):c.346C>T (p.Arg116Trp)

HGVS:

NC_000023.11:g.153932111G>A
NG_031987.1:g.8044C>T
NM_001256119.2:c.341+205C>T
NM_001256120.2:c.328C>T
NM_003491.4:c.346C>TMANE SELECT
NP_001243049.1:p.Arg110Trp
NP_003482.1:p.Arg116Trp
NC_000023.10:g.153197564G>A
NM_003491.3:c.346C>T

Protein change:

R110W; ARG116TRP

Links:

OMIM: 300013.0003

Molecular consequence:

NM_001256119.2:c.341+205C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001256120.2:c.328C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003491.4:c.346C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Ogden syndrome (OGDNS)
Synonyms:: N-terminal acetyltransferase deficiency
Identifiers:: MONDO: MONDO:0010457; MedGen: C3275447; Orphanet: 276432; OMIM: 300855

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000154971	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 31, 2016)	de novo	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 27094817 Citation Link,
SCV000257346	OMIM	no assertion criteria provided	Pathogenic (May 1, 2015)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 25099252, 23020937, 27094817
SCV000734762	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001429211	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 8, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002583290	Laboratory of Medical Genetics, University of Torino	no assertion criteria provided	Pathogenic (Oct 9, 2022)	de novo	research
SCV003807764	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 29, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003841901	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27094817, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

De novo missense mutations in the NAA10 gene cause severe non-syndromic developmental delay in males and females.

Popp B, Støve SI, Endele S, Myklebust LM, Hoyer J, Sticht H, Azzarello-Burri S, Rauch A, Arnesen T, Reis A.

Eur J Hum Genet. 2015 May;23(5):602-9. doi: 10.1038/ejhg.2014.150. Epub 2014 Aug 6.

PubMed [citation]

PMID:: 25099252
PMCID:: PMC4402627

Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.

Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, Albrecht B, Bartholdi D, Beygo J, Di Donato N, Dufke A, Cremer K, Hempel M, Horn D, Hoyer J, Joset P, Röpke A, Moog U, Riess A, Thiel CT, Tzschach A, Wiesener A, et al.

Lancet. 2012 Nov 10;380(9854):1674-82. doi: 10.1016/S0140-6736(12)61480-9. Epub 2012 Sep 27.

PubMed [citation]

PMID:: 23020937

See all PubMed Citations (4)

Details of each submission

From Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, SCV000154971.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From OMIM, SCV000257346.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

In a Swiss boy with a variant of Ogden syndrome (OGDNS; 300855), Popp et al. (2015) identified a de novo hemizygous c.346C-T transition (c.346C-T, NM_003491.3) in the NAA10 gene, resulting in an arg116-to-trp (R116W) substitution at a highly conserved residue in the N-acetyltransferase domain. The mutation, which was found by parent-child trio exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases or in an in-house control database. In vitro functional expression studies showed that the mutant protein had a small but significant reduction in catalytic activity (15% reduction compared to wildtype). The patient had previously been reported in a large exome sequencing study of patients with nonspecific severe intellectual disability (Rauch et al., 2012).

By trio exome sequencing in a female with OGDNS, Saunier et al. (2016) identified de novo heterozygosity for the R116W mutation in the NAA10 gene.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV000734762.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001429211.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Laboratory of Medical Genetics, University of Torino, SCV002583290.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807764.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 moderated

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From 3billion, SCV003841901.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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