4-2059665-C-A

Variant names:

• chr4-2059665-C-A
• rs1394330348
• NM_178557.4:c.154C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178557.4(NAT8L):​c.154C>A​(p.Pro52Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000361 in 830,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P52S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: NAT8L NM_178557.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.531
• Publications: 0 publications found

Genes affected

NAT8L (HGNC:26742): (N-acetyltransferase 8 like) This gene encodes a single-pass membrane protein, which contains a conserved sequence of the GCN5 or NAT superfamily of N-acetyltransferases and is a member of the N-acyltransferase (NAT) superfamily. This protein is a neuron-specific protein and is the N-acetylaspartate (NAA) biosynthetic enzyme, catalyzing the NAA synthesis from L-aspartate and acetyl-CoA. NAA is a major storage and transport form of acetyl coenzyme A specific to the nervous system. The gene mutation results in primary NAA deficiency (hypoacetylaspartia). [provided by RefSeq, Dec 2010]

NAT8L Gene-Disease associations (from GenCC):

• N-acetylaspartate deficiency

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09405008).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178557.4. 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
	NAT8L	NM_178557.4	MANE Select	c.154C>A	p.Pro52Thr	missense	Exon 1 of 3	NP_848652.2	Q8N9F0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAT8L	ENST00000423729.3	TSL:1 MANE Select	c.154C>A	p.Pro52Thr	missense	Exon 1 of 3	ENSP00000413064.2	Q8N9F0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000361 AC: 3 AN: 830342 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 384532

African (AFR) AF: 0.00 AC: 0 AN: 15712

American (AMR) AF: 0.00 AC: 0 AN: 1264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5276

East Asian (EAS) AF: 0.00 AC: 0 AN: 3960

South Asian (SAS) AF: 0.00 AC: 0 AN: 17122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1632

European-Non Finnish (NFE) AF: 0.00000264 AC: 2 AN: 756702

Other (OTH) AF: 0.0000365 AC: 1 AN: 27406

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.53
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.060	N
REVEL	Benign	0.028
Sift	Benign	0.17	T
Sift4G	Benign	0.44	T
Vest4		0.14
MutPred		0.26		Loss of glycosylation at P56 (P = 0.0015)
MVP		0.23
MPC		1.0
ClinPred		0.044	T
GERP RS		-1.0
PromoterAI		0.093	Neutral
Varity_R		0.063
gMVP		0.33
Mutation Taster		=90/10	polymorphism

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: rs1394330348; hg19: chr4-2061392;