rs587777212

Variant names:

• chr4-2059711-CGGGGGGCGCGGGGCCGCCG-C
• rs587777212
• NM_178557.4:c.212_230delGGCCGCCGGGGGGGCGCGG

Variant summary

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

The ENST00000423729.3(NAT8L):​c.212_230delGGCCGCCGGGGGGGCGCGG​(p.Gly71AlafsTer55) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000106 in 939,296 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as no classifications from unflagged records (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: NAT8L ENST00000423729.3 frameshift
• Clinical Significance: no classifications from unflagged records no classifications from unflagged records P:1
• Conservation: PhyloP100: 5.33
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000423729.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAT8L	NM_178557.4	MANE Select	c.212_230delGGCCGCCGGGGGGGCGCGG	p.Gly71AlafsTer55	frameshift	Exon 1 of 3	NP_848652.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAT8L	ENST00000423729.3	TSL:1 MANE Select	c.212_230delGGCCGCCGGGGGGGCGCGG	p.Gly71AlafsTer55	frameshift	Exon 1 of 3	ENSP00000413064.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000106 AC: 1 AN: 939296 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 446944

⚠️ 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: 18152

American (AMR) AF: 0.00 AC: 0 AN: 4094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8442

East Asian (EAS) AF: 0.00 AC: 0 AN: 13174

South Asian (SAS) AF: 0.00 AC: 0 AN: 20892

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2226

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 827340

Other (OTH) AF: 0.00 AC: 0 AN: 33614

⚠️ 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 Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: no classifications from unflagged records

Revision: no classifications from unflagged records

Pathogenic	VUS	Benign	Condition
1	-	-	N-acetylaspartate deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.3
Mutation Taster		=15/185	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587777212; hg19: chr4-2061438;