NM_178557.4:c.71C>T

Variant names:

• chr4-2059582-C-T
• rs1424083661
• NM_178557.4:c.71C>T

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.71C>T​(p.Pro24Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000202 in 990,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. P24R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: NAT8L NM_178557.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.44
• 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=0.15320727).

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.71C>T	p.Pro24Leu	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.71C>T	p.Pro24Leu	missense	Exon 1 of 3	ENSP00000413064.2	Q8N9F0

Frequencies

GnomAD3 genomes AF: 0.00000690 AC: 1 AN: 144932 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000153

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000118 AC: 1 AN: 845388 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 392434

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 15978

American (AMR) AF: 0.00 AC: 0 AN: 1498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5906

East Asian (EAS) AF: 0.00 AC: 0 AN: 3802

South Asian (SAS) AF: 0.00 AC: 0 AN: 19302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2652

European-Non Finnish (NFE) AF: 0.00000130 AC: 1 AN: 767460

Other (OTH) AF: 0.00 AC: 0 AN: 27850

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000690 AC: 1 AN: 144932 Hom.: 0 Cov.: 31 AF XY: 0.0000142 AC XY: 1 AN XY: 70458

African (AFR) AF: 0.00 AC: 0 AN: 40360

American (AMR) AF: 0.00 AC: 0 AN: 14678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3382

East Asian (EAS) AF: 0.00 AC: 0 AN: 4936

South Asian (SAS) AF: 0.00 AC: 0 AN: 4750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.0000153 AC: 1 AN: 65396

Other (OTH) AF: 0.00 AC: 0 AN: 1996

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.073
Eigen_PC	Benign	-0.085
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.4
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.026
Sift	Benign	0.030	D
Sift4G	Uncertain	0.012	D
Vest4		0.15
MutPred		0.26		Gain of helix (P = 0.0128)
MVP		0.43
MPC		0.94
ClinPred		0.27	T
GERP RS		2.4
PromoterAI		0.013	Neutral
Varity_R		0.078
gMVP		0.46
Mutation Taster		=51/49	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: rs1424083661; hg19: chr4-2061309;