chr4-2059607-C-T

Variant names:

• chr4-2059607-C-T
• rs183901937
• NM_178557.4:c.96C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_178557.4(NAT8L):​c.96C>T​(p.Leu32Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.022 in 979,798 control chromosomes in the GnomAD database, including 351 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.024 (113 hom., cov: 31)
  • Exomes 𝑓: 0.022 (238 hom.)
• Consequence: NAT8L NM_178557.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.316
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 4-2059607-C-T is Benign according to our data. Variant chr4-2059607-C-T is described in ClinVar as Benign. ClinVar VariationId is 3060891.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.316 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

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.96C>T	p.Leu32Leu	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.96C>T	p.Leu32Leu	synonymous	Exon 1 of 3	ENSP00000413064.2	Q8N9F0

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3412 AN: 144300 Hom.: 106 Cov.: 31

Gnomad AFR AF: 0.00360

Gnomad AMI AF: 0.00226

Gnomad AMR AF: 0.0255

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.0722

Gnomad MID AF: 0.00658

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0246

GnomAD2 exomes AF: 0.0325 AC: 32 AN: 986 AF XY: 0.0367

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0270

Gnomad EAS exome AF: 0.400

Gnomad FIN exome AF: 0.0513

Gnomad NFE exome AF: 0.0341

Gnomad OTH exome AF: 0.0385

GnomAD4 exome AF: 0.0217 AC: 18088 AN: 835396 Hom.: 238 Cov.: 29 AF XY: 0.0215 AC XY: 8307 AN XY: 386152

African (AFR) AF: 0.00177 AC: 28 AN: 15804

American (AMR) AF: 0.0287 AC: 31 AN: 1080

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 96 AN: 5268

East Asian (EAS) AF: 0.158 AC: 581 AN: 3672

South Asian (SAS) AF: 0.0107 AC: 188 AN: 17574

European-Finnish (FIN) AF: 0.0594 AC: 24 AN: 404

Middle Eastern (MID) AF: 0.0129 AC: 27 AN: 2100

European-Non Finnish (NFE) AF: 0.0215 AC: 16384 AN: 762102

Other (OTH) AF: 0.0266 AC: 729 AN: 27392

GnomAD4 genome AF: 0.0238 AC: 3437 AN: 144402 Hom.: 113 Cov.: 31 AF XY: 0.0257 AC XY: 1808 AN XY: 70226

African (AFR) AF: 0.00359 AC: 145 AN: 40342

American (AMR) AF: 0.0258 AC: 377 AN: 14638

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 59 AN: 3348

East Asian (EAS) AF: 0.157 AC: 766 AN: 4872

South Asian (SAS) AF: 0.0106 AC: 50 AN: 4714

European-Finnish (FIN) AF: 0.0722 AC: 590 AN: 8170

Middle Eastern (MID) AF: 0.00709 AC: 2 AN: 282

European-Non Finnish (NFE) AF: 0.0211 AC: 1376 AN: 65132

Other (OTH) AF: 0.0347 AC: 70 AN: 2018

Alfa AF: 0.0241 Hom.: 12

Bravo AF: 0.0217

Asia WGS AF: 0.0730 AC: 131 AN: 1810

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	NAT8L-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	13
DANN	Benign	0.93
PhyloP100		-0.32
PromoterAI		0.0054	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: rs183901937; hg19: chr4-2061334; COSMIC: COSV59050769; COSMIC: COSV59050769;