NM_003491.4:c.346C>T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 7.30

Variant links:

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 links:

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 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
NAA10	NM_003491.4 link	c.346C>T	p.Arg116Trp	missense_variant	Exon 6 of 8	ENST00000464845.6	NP_003482.1	P41227-1
NAA10	NM_001256120.2 link	c.328C>T	p.Arg110Trp	missense_variant	Exon 6 of 8		NP_001243049.1	B7Z9N2
NAA10	NM_001256119.2 link	c.341+205C>T		intron_variant	Intron 5 of 6		NP_001243048.1	P41227-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAA10	ENST00000464845.6 link	c.346C>T	p.Arg116Trp	missense_variant	Exon 6 of 8	1	NM_003491.4	ENSP00000417763.1		P41227-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ogden syndrome

Pathogenic:7

May 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 29, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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

- -

Oct 09, 2022

Laboratory of Medical Genetics, University of Torino

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Aug 08, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Pathogenic:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 28, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

NAA10-related disorder

Pathogenic:2

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 04, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;.;.;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.83

D;D;D;D

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.6

L;.;.;.

PrimateAI

Pathogenic

0.85

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over