4-2059624-T-C

Variant names:

• chr4-2059624-T-C
• rs1054562888
• NM_178557.4:c.113T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178557.4(NAT8L):​c.113T>C​(p.Met38Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 831,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: NAT8L NM_178557.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21237826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAT8L	NM_178557.4	c.113T>C	p.Met38Thr	missense_variant	Exon 1 of 3	ENST00000423729.3	NP_848652.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAT8L	ENST00000423729.3	c.113T>C	p.Met38Thr	missense_variant	Exon 1 of 3	1	NM_178557.4	ENSP00000413064.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000192 AC: 16 AN: 831404 Hom.: 0 Cov.: 23 AF XY: 0.0000234 AC XY: 9 AN XY: 384202

Gnomad4 AFR exome AF: 0.0000635

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: 0.0000184

Gnomad4 OTH exome AF: 0.0000367

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.113T>C (p.M38T) alteration is located in exon 1 (coding exon 1) of the NAT8L gene. This alteration results from a T to C substitution at nucleotide position 113, causing the methionine (M) at amino acid position 38 to be replaced by a threonine (T). 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	Benign	0.24
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.72
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.045
Eigen_PC	Benign	-0.069
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.31	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.050
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.56	T
Vest4		0.24
MutPred		0.28		Loss of glycosylation at P41 (P = 0.0092);
MVP		0.60
MPC		1.1
ClinPred		0.23	T
GERP RS		2.4
Varity_R		0.76
gMVP		0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs1054562888; hg19: chr4-2061351;