chr4-2059616-C-T

Variant names:

• chr4-2059616-C-T
• rs765315001
• NM_178557.4:c.105C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_178557.4(NAT8L):​c.105C>T​(p.Ala35Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000733 in 980,076 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (7 hom.)
• Consequence: NAT8L NM_178557.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.463
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 4-2059616-C-T is Benign according to our data. Variant chr4-2059616-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 781845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.463 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 7 AR,Unknown gene

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.105C>T	p.Ala35Ala	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.105C>T	p.Ala35Ala	synonymous	Exon 1 of 3	ENSP00000413064.2	Q8N9F0

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 204 AN: 145442 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0475

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000549

Gnomad OTH AF: 0.00100

GnomAD2 exomes AF: 0.00 AC: 0 AN: 632 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000616 AC: 514 AN: 834634 Hom.: 7 Cov.: 26 AF XY: 0.000547 AC XY: 211 AN XY: 385732

African (AFR) AF: 0.00 AC: 0 AN: 15794

American (AMR) AF: 0.00 AC: 0 AN: 1054

Ashkenazi Jewish (ASJ) AF: 0.0495 AC: 258 AN: 5208

East Asian (EAS) AF: 0.00 AC: 0 AN: 3642

South Asian (SAS) AF: 0.00 AC: 0 AN: 17422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 354

Middle Eastern (MID) AF: 0.000512 AC: 1 AN: 1952

European-Non Finnish (NFE) AF: 0.000211 AC: 161 AN: 761842

Other (OTH) AF: 0.00343 AC: 94 AN: 27366

GnomAD4 genome AF: 0.00140 AC: 204 AN: 145442 Hom.: 7 Cov.: 32 AF XY: 0.00124 AC XY: 88 AN XY: 70720

African (AFR) AF: 0.000123 AC: 5 AN: 40616

American (AMR) AF: 0.00 AC: 0 AN: 14672

Ashkenazi Jewish (ASJ) AF: 0.0475 AC: 161 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 5000

South Asian (SAS) AF: 0.00 AC: 0 AN: 4754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.000549 AC: 36 AN: 65550

Other (OTH) AF: 0.00100 AC: 2 AN: 2000

Alfa AF: 0.00187 Hom.: 0

Bravo AF: 0.00123

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	-0.53
CADD	Benign	15
DANN	Benign	0.94
PhyloP100		-0.46
PromoterAI		-0.062	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: rs765315001; hg19: chr4-2061343;