rs587782992

Positions:

• chr5-140114482-ACT-A
• chr5-140114482-ACT-ACTCT

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_005859.5(PURA):​c.307_308delTC​(p.Ser103fs) variant causes a frameshift change. 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, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.98

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 14 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 17 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-140114482-ACT-A is Pathogenic according to our data. Variant chr5-140114482-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 156404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-140114482-ACT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PURA	NM_005859.5	c.307_308delTC	p.Ser103fs	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.307_308delTC	p.Ser103fs	frameshift_variant	1/1	6	NM_005859.5	ENSP00000332706.3
PURA	ENST00000651386.1	c.307_308delTC	p.Ser103fs	frameshift_variant	2/2			ENSP00000499133.1
PURA	ENST00000505703.2	c.307_308delTC	p.Ser103fs	frameshift_variant	2/2	3		ENSP00000498560.1

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

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 17, 2023	Criteria applied: PVS1,PS2,PS4_MOD,PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 06, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 17, 2018	For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Asp207Thrfs*16) that lies downstream of this variant has been determined to be pathogenic (Invitae). This suggests that deletion of this region of the PURA protein is causative of disease. This variant has been observed to be de novo in individuals affected with early infantile epileptic encephalopathy (PMID: 25439098). This variant has also been observed in an individual affected with gross motor delay, hypotonia, and seizures (PMID: 28600779). This variant is also known as c.302_303del in the literature. ClinVar contains an entry for this variant (Variation ID: 156404). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the PURA gene (p.Ser103Hisfs*97). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 221 amino acids of the PURA protein. -

Delayed speech and language development;C0557874:Global developmental delay;C2267233:Neonatal hypotonia;C3714756:Intellectual disability Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Whole genome laboratory; Baylor College of Medicine

Sep 15, 2014

- -

PURA-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2024

The PURA c.307_308delTC variant is predicted to result in a frameshift and premature protein termination (p.Ser103Hisfs*97). This variant has been reported in the de novo state in individuals with hypotonia, seizures, encephalopathy or developmental disorders (see for example, Lalani et al 2014. PubMed ID: 25439098; Table S1, Kaplanis et al. 2020. PubMed ID: 33057194). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in PURA are expected to be pathogenic. This variant is interpreted 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: rs587782992; hg19: chr5-139494067;