chr4-139351602-CAAAG-C

Variant names:

• chr4-139351602-CAAAG-C
• rs1553996086
• NM_057175.5:c.1009_1012delGAAA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_057175.5(NAA15):​c.1009_1012delGAAA​(p.Glu337ArgfsTer5) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAA15 NM_057175.5 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.48
• Publications: 1 publications found

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

ACMG classification

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 4-139351602-CAAAG-C is Pathogenic according to our data. Variant chr4-139351602-CAAAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 559846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAA15	NM_057175.5	c.1009_1012delGAAA	p.Glu337ArgfsTer5	frameshift_variant, splice_region_variant	Exon 9 of 20	ENST00000296543.10	NP_476516.1
NAA15	NM_001410842.1	c.1009_1012delGAAA	p.Glu337ArgfsTer5	frameshift_variant, splice_region_variant	Exon 9 of 20		NP_001397771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAA15	ENST00000296543.10	c.1009_1012delGAAA	p.Glu337ArgfsTer5	frameshift_variant, splice_region_variant	Exon 9 of 20	1	NM_057175.5	ENSP00000296543.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 50 Pathogenic:2

Jul 07, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 10, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS2, PS2, PS4, PM2 -

Inborn genetic diseases Pathogenic:1

Jul 19, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1009_1012delGAAA (p.E337Rfs*5) alteration, located in exon 9 (coding exon 9) of the NAA15 gene, consists of a deletion of 4 nucleotides from position 1009 to 1012, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with NAA15-related neurodevelopmental disorder (Zaidi, 2013; Cheng, 2018; Ritter, 2021). Functional analysis of patient derived cells showed degradation of the mutant NAA15 mRNA, suggesting nonsense-mediated decay (Cheng, 2018). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs1553996086; hg19: chr4-140272756;