NM_178557.4:c.168A>C

Variant names:

• chr4-2059679-A-C
• rs900199956
• NM_178557.4:c.168A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_178557.4(NAT8L):​c.168A>C​(p.Pro56Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 137,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NAT8L NM_178557.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.226
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 4-2059679-A-C is Benign according to our data. Variant chr4-2059679-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 727925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.226 with no splicing effect.

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.168A>C	p.Pro56Pro	synonymous	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.168A>C	p.Pro56Pro	synonymous	Exon 1 of 3	ENSP00000413064.2	Q8N9F0

Frequencies

GnomAD3 genomes AF: 0.000102 AC: 14 AN: 137082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000784

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000143

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000793

Gnomad FIN AF: 0.000132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000791

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000365 AC: 3 AN: 821890 Hom.: 0 Cov.: 19 AF XY: 0.00000521 AC XY: 2 AN XY: 384002

⚠️ 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: 15540

American (AMR) AF: 0.00 AC: 0 AN: 1844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5768

East Asian (EAS) AF: 0.00 AC: 0 AN: 5972

South Asian (SAS) AF: 0.00 AC: 0 AN: 16818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1726

European-Non Finnish (NFE) AF: 0.00000269 AC: 2 AN: 742930

Other (OTH) AF: 0.0000361 AC: 1 AN: 27680

⚠️ 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: 0.000102 AC: 14 AN: 137212 Hom.: 0 Cov.: 32 AF XY: 0.000105 AC XY: 7 AN XY: 66620

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

African (AFR) AF: 0.0000782 AC: 3 AN: 38346

American (AMR) AF: 0.000143 AC: 2 AN: 14030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3328

East Asian (EAS) AF: 0.00 AC: 0 AN: 3856

South Asian (SAS) AF: 0.000789 AC: 3 AN: 3800

European-Finnish (FIN) AF: 0.000132 AC: 1 AN: 7604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.0000791 AC: 5 AN: 63184

Other (OTH) AF: 0.00 AC: 0 AN: 1958

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.41
PhyloP100		-0.23
PromoterAI		0.11	Neutral
Mutation Taster		=100/0	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: rs900199956; hg19: chr4-2061406; COSMIC: COSV59051254; COSMIC: COSV59051254;