rs863225427

Positions:

• chrX-153933994-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The ENST00000464845.6(NAA10):​c.128A>C​(p.Tyr43Ser) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y43C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: NAA10 ENST00000464845.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.46

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000464845.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-153933994-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1705306.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant X-153933994-T-G is Pathogenic according to our data. Variant chrX-153933994-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 218104.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-153933994-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAA10	NM_003491.4	c.128A>C	p.Tyr43Ser	missense_variant	3/8	ENST00000464845.6	NP_003482.1
NAA10	NM_001256120.2	c.128A>C	p.Tyr43Ser	missense_variant	3/8		NP_001243049.1
NAA10	NM_001256119.2	c.128A>C	p.Tyr43Ser	missense_variant	3/7		NP_001243048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAA10	ENST00000464845.6	c.128A>C	p.Tyr43Ser	missense_variant	3/8	1	NM_003491.4	ENSP00000417763	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Ogden syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 02, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	32
DANN	Benign	0.97
DEOGEN2	Uncertain	0.54	D;.;.;.;.;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.7	M;.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.8	D;D;D;D;D;D
REVEL	Uncertain	0.59
Sift	Benign	0.053	T;T;D;T;D;D
Sift4G	Uncertain	0.050	T;T;T;D;.;.
Polyphen		0.78	P;.;.;.;.;.
Vest4		0.81
MutPred		0.72		Gain of disorder (P = 0.0047);Gain of disorder (P = 0.0047);Gain of disorder (P = 0.0047);Gain of disorder (P = 0.0047);Gain of disorder (P = 0.0047);Gain of disorder (P = 0.0047);
MVP		0.90
MPC		2.5
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: -33

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs863225427; hg19: chrX-153199447;