rs1057518605

Variant names:

• chrX-153930794-A-G
• rs1057518605
• NM_003491.4:c.440T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_003491.4(NAA10):​c.440T>C​(p.Met147Thr) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M147V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: NAA10 NM_003491.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 6.82
• Publications: 5 publications found

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]

ARHGAP4 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 26 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 2.408 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to NAA10-related syndrome, Ogden syndrome, microphthalmia, Lenz type, microphthalmia, syndromic 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant X-153930794-A-G is Pathogenic according to our data. Variant chrX-153930794-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 373777.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003491.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAA10	NM_003491.4	MANE Select	c.440T>C	p.Met147Thr	missense	Exon 7 of 8	NP_003482.1	P41227-1
	NAA10	NM_001256120.2		c.422T>C	p.Met141Thr	missense	Exon 7 of 8	NP_001243049.1
	NAA10	NM_001256119.2		c.395T>C	p.Met132Thr	missense	Exon 6 of 7	NP_001243048.1	P41227-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAA10	ENST00000464845.6	TSL:1 MANE Select	c.440T>C	p.Met147Thr	missense	Exon 7 of 8	ENSP00000417763.1	P41227-1
	NAA10	ENST00000370009.5	TSL:1	c.395T>C	p.Met132Thr	missense	Exon 6 of 7	ENSP00000359026.1	P41227-2
	NAA10	ENST00000466877.5	TSL:1	n.751T>C		non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)
-	1	-	Microphthalmia, syndromic 1;C3275447:Ogden syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.79	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		6.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.64		Gain of phosphorylation at M147 (P = 0.0078)
MVP		0.58
MPC		3.3
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.94
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057518605; hg19: chrX-153196247;