dbSNP rs1380822792: NAA15:p.Asp76GlufsTer20 (chr4-139336932-ATGACT-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_057175.5(NAA15):c.228_232delCTTGA(p.Asp76GlufsTer20) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,160 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NAA15
NM_057175.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 9.60

Publications

3 publications found

Variant links:

Genes affected

NAA15 (HGNC:30782): (N-alpha-acetyltransferase 15, NatA auxiliary subunit) N-alpha-acetylation is among the most common post-translational protein modifications in eukaryotic cells. This process involves the transfer of an acetyl group from acetyl-coenzyme A to the alpha-amino group on a nascent polypeptide and is essential for normal cell function. This gene encodes the auxillary subunit of the N-terminal acetyltransferase A (NatA) complex. [provided by RefSeq, Jan 2017]

NAA15 Gene-Disease associations (from GenCC):

intellectual disability, autosomal dominant 50
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

NAA15 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-139336932-ATGACT-A is Pathogenic according to our data. Variant chr4-139336932-ATGACT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 446520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_057175.5. 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
	NAA15	NM_057175.5	MANE Select	c.228_232delCTTGA	p.Asp76GlufsTer20	frameshift	Exon 3 of 20	NP_476516.1	Q9BXJ9-1
	NAA15	NM_001410842.1		c.228_232delCTTGA	p.Asp76GlufsTer20	frameshift	Exon 3 of 20	NP_001397771.1	A0A0B4J1W3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NAA15	ENST00000296543.10	TSL:1 MANE Select	c.228_232delCTTGA	p.Asp76GlufsTer20	frameshift	Exon 3 of 20	ENSP00000296543.4	Q9BXJ9-1
NAA15	ENST00000398947.1	TSL:5	c.228_232delCTTGA	p.Asp76GlufsTer20	frameshift	Exon 3 of 20	ENSP00000381920.1	A0A0B4J1W3
NAA15	ENST00000920374.1		c.228_232delCTTGA	p.Asp76GlufsTer20	frameshift	Exon 3 of 20	ENSP00000590433.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447160

Hom.:

AF XY:

0.00

AC XY:

AN XY:

719802

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32892

American (AMR)

AF:

0.00

AC:

AN:

43022

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25814

East Asian (EAS)

AF:

0.00

AC:

AN:

38758

South Asian (SAS)

AF:

0.00

AC:

AN:

83802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52958

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1104552

Other (OTH)

AF:

0.00

AC:

AN:

59632

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability, autosomal dominant 50 (5)

not provided (3)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.6

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over