16-3483377-G-A

Variant names:

• chr16-3483377-G-A
• NM_001083601.3:c.352G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001083601.3(NAA60):​c.352G>A​(p.Glu118Lys) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E118Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAA60 NM_001083601.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.46
• Publications: 0 publications found

Genes affected

NAA60 (HGNC:25875): (N-alpha-acetyltransferase 60, NatF catalytic subunit) This gene encodes an enzyme that localizes to the Golgi apparatus, where it transfers an acetyl group to the N-terminus of free proteins. This enzyme acts on histones, and its activity is important for chromatin assembly and chromosome integrity. Alternative splicing and the use of alternative promoters results in multiple transcript variants. The upstream promoter is located in a differentially methylated region (DMR) and undergoes imprinting; transcript variants originating from this position are expressed from the maternal allele. [provided by RefSeq, Nov 2015]

NAA60 Gene-Disease associations (from GenCC):

• basal ganglia calcification, idiopathic, 9, autosomal recessive

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ENSG00000263212 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a domain N-acetyltransferase (size 169) in uniprot entity NAA60_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001083601.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3813491).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAA60	NM_001083601.3	c.352G>A	p.Glu118Lys	missense_variant	Exon 6 of 8	ENST00000407558.9	NP_001077070.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAA60	ENST00000407558.9	c.352G>A	p.Glu118Lys	missense_variant	Exon 6 of 8	1	NM_001083601.3	ENSP00000385903.4
NAA60	ENST00000424546.6	c.373G>A	p.Glu125Lys	missense_variant	Exon 5 of 7	2		ENSP00000401237.2
NAA60	ENST00000414063.6	c.352G>A	p.Glu118Lys	missense_variant	Exon 5 of 7	2		ENSP00000393224.2
NAA60	ENST00000360862.9	c.157G>A	p.Glu53Lys	missense_variant	Exon 4 of 6	2		ENSP00000354108.5
NAA60	ENST00000573580.5	c.157G>A	p.Glu53Lys	missense_variant	Exon 4 of 5	4		ENSP00000459055.1
NAA60	ENST00000572739.5	n.255G>A		non_coding_transcript_exon_variant	Exon 4 of 5	4		ENSP00000461438.1
NAA60	ENST00000573345.5	n.*96G>A		non_coding_transcript_exon_variant	Exon 4 of 5	4		ENSP00000458717.1
NAA60	ENST00000573345.5	n.*96G>A		3_prime_UTR_variant	Exon 4 of 5	4		ENSP00000458717.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.352G>A (p.E118K) alteration is located in exon 6 (coding exon 4) of the NAA60 gene. This alteration results from a G to A substitution at nucleotide position 352, causing the glutamic acid (E) at amino acid position 118 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	Pathogenic	0.83
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T;.;T;.;T;.;T;T;T;.;.;T;T;T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D;D;D;.;.;.;.;D;.;D;.;.;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.53	N;.;.;.;N;.;N;N;.;.;.;N;N;N;.
PhyloP100		9.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.3	N;.;.;N;.;.;.;.;.;N;.;N;.;.;.
REVEL	Benign	0.19
Sift	Uncertain	0.017	D;.;.;D;.;.;.;.;.;D;.;D;.;.;.
Sift4G	Benign	0.070	T;T;D;T;.;T;.;.;D;T;.;T;T;T;D
Polyphen		0.12	B;.;.;.;B;.;B;B;.;.;.;B;B;B;.
Vest4		0.53
MutPred		0.45		Gain of MoRF binding (P = 0.0604);Gain of MoRF binding (P = 0.0604);Gain of MoRF binding (P = 0.0604);.;Gain of MoRF binding (P = 0.0604);.;Gain of MoRF binding (P = 0.0604);Gain of MoRF binding (P = 0.0604);Gain of MoRF binding (P = 0.0604);.;.;Gain of MoRF binding (P = 0.0604);Gain of MoRF binding (P = 0.0604);Gain of MoRF binding (P = 0.0604);Gain of MoRF binding (P = 0.0604);
MVP		0.043
MPC		0.47
ClinPred		0.91	D
GERP RS		5.5
Varity_R		0.75
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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

hg19: chr16-3533377;