X-153930109-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_003491.4(NAA10):c.586G>A(p.Glu196Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000108 in 1,208,804 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000011 (0 hom. 5 hem.)
• Consequence: NAA10 NM_003491.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.09

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 0 ACMG points.

• PM1: In a chain N-alpha-acetyltransferase 10 (size 234) in uniprot entity NAA10_HUMAN there are 32 pathogenic changes around while only 4 benign (89%) in NM_003491.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.23812935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAA10	NM_003491.4	c.586G>A	p.Glu196Lys	missense_variant	8/8	ENST00000464845.6
NAA10	NM_001256120.2	c.568G>A	p.Glu190Lys	missense_variant	8/8
NAA10	NM_001256119.2	c.541G>A	p.Glu181Lys	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAA10	ENST00000464845.6	c.586G>A	p.Glu196Lys	missense_variant	8/8	1	NM_003491.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000903 AC: 1 AN: 110785 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 32961

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 12 AN: 1098019 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 363381

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: 0.0000119

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome AF: 0.00000903 AC: 1 AN: 110785 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 32961

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

The c.586G>A (p.E196K) alteration is located in exon 8 (coding exon 8) of the NAA10 gene. This alteration results from a G to A substitution at nucleotide position 586, causing the glutamic acid (E) at amino acid position 196 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.43	N;N
REVEL	Benign	0.043
Sift	Benign	0.031	D;D
Sift4G	Benign	0.33	T;T
Polyphen		0.050	B;.
Vest4		0.25
MutPred		0.18		Gain of ubiquitination at E196 (P = 0.0031);.;
MVP		0.88
MPC		0.68
ClinPred		0.89	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.60

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: rs1224673873; hg19: chrX-153195562; COSMIC: COSV63130857; COSMIC: COSV63130857;