5-140114199-CG-C

Variant summary

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

The NM_005859.5(PURA):c.20del(p.Gly7AlafsTer71) 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: 31)
• Consequence: PURA NM_005859.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.53

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 147 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-140114199-CG-C is Pathogenic according to our data. Variant chr5-140114199-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 2807067.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PURA	NM_005859.5	c.20del	p.Gly7AlafsTer71	frameshift_variant	1/1	ENST00000331327.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PURA	ENST00000331327.5	c.20del	p.Gly7AlafsTer71	frameshift_variant	1/1		NM_005859.5	P1
PURA	ENST00000651386.1	c.20del	p.Gly7AlafsTer71	frameshift_variant	2/2			P1
PURA	ENST00000505703.2	c.20del	p.Gly7AlafsTer71	frameshift_variant	2/2	3
PURA	ENST00000502351.1	c.20del	p.Gly7AlafsTer?	frameshift_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 10

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 28, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PURA protein in which other variant(s) (p.Thr310Asnfs*7) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with PURA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly7Alafs*71) in the PURA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 316 amino acid(s) of the PURA protein. -

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-139493784;