rs1554129039

Variant names:

• chr5-140114333-CA-C
• rs1554129039
• NM_005859.5:c.153delA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005859.5(PURA):​c.153delA​(p.Leu54CysfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PURA NM_005859.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.359

Genes affected

PURA (HGNC:9701): (purine rich element binding protein A) This gene product is a sequence-specific, single-stranded DNA-binding protein. It binds preferentially to the single strand of the purine-rich element termed PUR, which is present at origins of replication and in gene flanking regions in a variety of eukaryotes from yeasts through humans. Thus, it is implicated in the control of both DNA replication and transcription. Deletion of this gene has been associated with myelodysplastic syndrome and acute myelogenous leukemia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 22 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-140114333-CA-C is Pathogenic according to our data. Variant chr5-140114333-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 522145.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PURA	NM_005859.5	c.153delA	p.Leu54CysfsTer24	frameshift_variant	Exon 1 of 1	ENST00000331327.5	NP_005850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PURA	ENST00000331327.5	c.153delA	p.Leu54CysfsTer24	frameshift_variant	Exon 1 of 1	6	NM_005859.5	ENSP00000332706.3
PURA	ENST00000651386.1	c.153delA	p.Leu54CysfsTer24	frameshift_variant	Exon 2 of 2			ENSP00000499133.1
PURA	ENST00000505703.2	c.153delA	p.Leu54CysfsTer24	frameshift_variant	Exon 2 of 2	3		ENSP00000498560.1
PURA	ENST00000502351.1	c.*74delA		downstream_gene_variant		2		ENSP00000498760.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Sep 13, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.153delA (p.L54Cfs*24) alteration, located in coding exon 1 of the PURA gene, consists of a deletion of one nucleotide at position 153, causing a translational frameshift with a predicted alternate stop codon after 24 amino acids. Frameshifts are typically deleterious in nature; however, because PURA is a single-exon gene this alteration is not expected to trigger nonsense-mediated mRNA decay and a truncated protein could still be expressed (Maquat, 2004). This alteration removes the last 83.5% of the protein. The exact functional impact of these amino acids is unknown at this time; however, a significant portion of the protein is affected (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with features consistent with PURA-related neurodevelopmental disorder (Nogueira, 2022; Reijnders, 2018). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554129039; hg19: chr5-139493918;