chr14-57391409-C-A

Position:

• chr14-57391409-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001011713.3(NAA30):​c.452C>A​(p.Pro151His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NAA30 NM_001011713.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.01

Genes affected

NAA30 (HGNC:19844): (N-alpha-acetyltransferase 30, NatC catalytic subunit) Enables peptide alpha-N-acetyltransferase activity. Involved in N-terminal peptidyl-methionine acetylation. Located in cytosol and nucleus. Part of NatC complex. Colocalizes with polysome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-57391409-C-A is Pathogenic according to our data. Variant chr14-57391409-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 984533.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17801017). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAA30	NM_001011713.3	c.452C>A	p.Pro151His	missense_variant	2/5	ENST00000556492.6	NP_001011713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAA30	ENST00000556492.6	c.452C>A	p.Pro151His	missense_variant	2/5	1	NM_001011713.3	ENSP00000452521.1
NAA30	ENST00000298406.6	c.107C>A	p.Pro36His	missense_variant	1/4	1		ENSP00000298406.6
NAA30	ENST00000554703.1	c.-4+704C>A		intron_variant		1		ENSP00000451255.1
NAA30	ENST00000555166.5	c.-4+704C>A		intron_variant		2		ENSP00000450939.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455230 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723568

Gnomad4 AFR exome AF: 0.0000300

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lethal multiystemic syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing;in vitro;research

Centre de Genetique Humaine, Institut de Pathologie et de Genetique

-

NAA30 gene is not yet known as a causal gene for human disease. It codes the catalytic subunit of the NatC complex. From a cellular perspective, NatC plays a role in maintaining normal mitochondrial function, as depletion of NAA30 causes mitochondrial fragmentation, reduced membrane potential as well as reduced expression levels of processed mitochondrial matrix proteins in human cancer cell lines .The importance of NatC in embryonic development was already reported in 2006. Morpholino-induced knockdown of NAA30 and NAA35 in zebrafish revealed severe growth and development delay leading to embryonic lethality. Mutations in NAA38 and NAA35 were already described in patients with developmental delay. Here we report the homozygous c.452C>A p.(P151H) variant in NAA30 in a boy with severe hypotonia, developmental delay, hepatosplenomegaly, congenital mixed hearing loss and bilateral optic nerve atrophy, severe feeding difficulties, growth delay with relative macrocephaly, progressive coarsening of face, diffuse cerebral atrophy, and recurrent respiratory infections. Muscle biopsy revealed abnormal mitochondrial morphology with focal vanishing of mitochondrial ridges, intramitochondrial glycogen inclusions and rupture of the outer mitochondrial membrane. Functional characterization of NAA30-P151H by in vitro enzymatic assays revealed a reduced catalytic activity towards a NatC-type substrate. In summary, we consider the c.452C>A p.(P151H) variant in NAA30 as likely pathogenic based upon functional evidence, thereby linking the NatC complex to a N-terminal acetylation deficiency related syndrome. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.053	T
Eigen	Benign	0.062
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.088
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.042	D
Polyphen		0.61	P
Vest4		0.27
MutPred		0.28		Loss of loop (P = 0.0128);
MVP		0.068
MPC		1.3
ClinPred		0.90	D
GERP RS		3.6
Varity_R		0.24
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-57858127;