rs1554129040

Positions:

• chr5-140114334-A-AG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005859.5(PURA):​c.159dup​(p.Leu54AlafsTer147) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000777 in 1,287,560 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: PURA NM_005859.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.70

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 18 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 5-140114334-A-AG is Pathogenic according to our data. Variant chr5-140114334-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 432233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PURA	NM_005859.5	c.159dup	p.Leu54AlafsTer147	frameshift_variant	1/1	ENST00000331327.5	NP_005850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PURA	ENST00000331327.5	c.159dup	p.Leu54AlafsTer147	frameshift_variant	1/1		NM_005859.5	ENSP00000332706	P1
PURA	ENST00000505703.2	c.159dup	p.Leu54AlafsTer?	frameshift_variant	2/2	3		ENSP00000498560
PURA	ENST00000651386.1	c.159dup	p.Leu54AlafsTer147	frameshift_variant	2/2			ENSP00000499133	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.77e-7 AC: 1 AN: 1287560 Hom.: 0 Cov.: 33 AF XY: 0.00000157 AC XY: 1 AN XY: 636982

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.71e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000432233, PMID:32581362). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2022	ClinVar contains an entry for this variant (Variation ID: 432233). This premature translational stop signal has been observed in individual(s) with clinical features of PURA-related conditions (PMID: 32581362). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu54Alafs*147) in the PURA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 269 amino acid(s) of the PURA protein. This variant disrupts a region of the PURA protein in which other variant(s) (p.Tyr240*) 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. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2021	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 269 amino acids are lost and replaced with 146 incorrect amino acids.; Not observed in large population cohorts (Lek et al., 2016); Reported in a large cohort of individuals with rare disease, but clinical information is not provided (Turro et al., 2020); This variant is associated with the following publications: (PMID: 32581362) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Intellectual disability Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

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- -

PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 18, 2016

The p.Leu54fs variant in PURA has not been previously reported in individuals wi th severe neonatal hypotonia-seizures-encephalopathy syndrome. Data from large p opulation studies is insufficient to assess the frequency of this variant. The p .Leu54fs variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 54 and leads to a premature terminatio n codon 147 amino acids downstream. This gene contains a single exon, so the alt ered transcript is more likely to escape nonsense mediated decay (NMD) and resul t in a truncated protein. Heterozygous truncating variants in the PURA gene are strongly associated with severe neonatal hypotonia-seizures-encephalopathy syndr ome, with the all causative variants reported to date occuring de novo. In summa ry, the p.Leu54fs variant meets criteria to be classified as pathogenic for seve re neonatal hypotonia-seizures-encephalopathy syndrome based on its predicted im pact to the 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

LitVar

Other links and lift over

dbSNP: rs1554129040; hg19: chr5-139493919;