rs387906701

Variant names:

• chrX-153934388-A-G
• rs387906701
• NM_003491.4:c.109T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_003491.4(NAA10):​c.109T>C​(p.Ser37Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: NAA10 NM_003491.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.51

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-153934388-A-G is Pathogenic according to our data. Variant chrX-153934388-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 29927.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153934388-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAA10	NM_003491.4	c.109T>C	p.Ser37Pro	missense_variant	Exon 2 of 8	ENST00000464845.6	NP_003482.1
NAA10	NM_001256120.2	c.109T>C	p.Ser37Pro	missense_variant	Exon 2 of 8		NP_001243049.1
NAA10	NM_001256119.2	c.109T>C	p.Ser37Pro	missense_variant	Exon 2 of 7		NP_001243048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAA10	ENST00000464845.6	c.109T>C	p.Ser37Pro	missense_variant	Exon 2 of 8	1	NM_003491.4	ENSP00000417763.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ogden syndrome Pathogenic:1

Jul 15, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Microphthalmia, syndromic 1 Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.109T>C (p.Ser37Pro) variant in NAA10 gene has been reported in multiple individuals from two families affected with NAA10-related Ogden syndrome (Rope et al., 2011). It has also been observed to segregate with disease in related individuals (Rope et al., 2011). Experimental studies showed that this variant impairs both NatA complex formation and NatA catalytic activity (Myklebust et al., 2015). This variant is absent in the gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic. Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position in NAA10 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 37 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;.;.;.;T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.4	M;.;.;M;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.6	D;D;D;D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;.;.
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.86
MutPred		0.48		Loss of relative solvent accessibility (P = 0.0793);Loss of relative solvent accessibility (P = 0.0793);Loss of relative solvent accessibility (P = 0.0793);Loss of relative solvent accessibility (P = 0.0793);Loss of relative solvent accessibility (P = 0.0793);Loss of relative solvent accessibility (P = 0.0793);
MVP		0.67
MPC		3.4
ClinPred		0.99	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.98

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: rs387906701; hg19: chrX-153199841;