chrX-153930166-C-G

Position:

• chrX-153930166-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The ENST00000464845.6(NAA10):​c.529G>C​(p.Glu177Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,994 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: NAA10 ENST00000464845.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.71

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 2 ACMG points.

• PM1: In a chain N-alpha-acetyltransferase 10 (size 234) in uniprot entity NAA10_HUMAN there are 45 pathogenic changes around while only 5 benign (90%) in ENST00000464845.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23281366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAA10	NM_003491.4	c.529G>C	p.Glu177Gln	missense_variant	8/8	ENST00000464845.6	NP_003482.1
NAA10	NM_001256120.2	c.511G>C	p.Glu171Gln	missense_variant	8/8		NP_001243049.1
NAA10	NM_001256119.2	c.484G>C	p.Glu162Gln	missense_variant	7/7		NP_001243048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAA10	ENST00000464845.6	c.529G>C	p.Glu177Gln	missense_variant	8/8	1	NM_003491.4	ENSP00000417763	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000551 AC: 1 AN: 181389 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66445

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097994 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363370

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

NAA10-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 09, 2024

The NAA10 c.529G>C variant is predicted to result in the amino acid substitution p.Glu177Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.013	D;D
Sift4G	Benign	0.083	T;T
Polyphen		0.98	D;.
Vest4		0.19
MutPred		0.27		Gain of MoRF binding (P = 0.0256);.;
MVP		0.80
MPC		0.65
ClinPred		0.70	D
GERP RS		4.6
Varity_R		0.37
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1557107145; hg19: chrX-153195619;