rs1553996086

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.

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.1009_1012delGAAA	p.Glu337ArgfsTer5	frameshift splice_region	Exon 9 of 20	NP_476516.1	Q9BXJ9-1
	NAA15	NM_001410842.1		c.1009_1012delGAAA	p.Glu337ArgfsTer5	frameshift splice_region	Exon 9 of 20	NP_001397771.1	A0A0B4J1W3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAA15	ENST00000296543.10	TSL:1 MANE Select	c.1009_1012delGAAA	p.Glu337ArgfsTer5	frameshift splice_region	Exon 9 of 20	ENSP00000296543.4	Q9BXJ9-1
	NAA15	ENST00000398947.1	TSL:5	c.1009_1012delGAAA	p.Glu337ArgfsTer5	frameshift splice_region	Exon 9 of 20	ENSP00000381920.1	A0A0B4J1W3
	NAA15	ENST00000920374.1		c.1009_1012delGAAA	p.Glu337ArgfsTer5	frameshift splice_region	Exon 9 of 20	ENSP00000590433.1

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Intellectual disability, autosomal dominant 50 (2)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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;