rs786204835
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong
The NM_005859.5(PURA):c.697_699delTTC(p.Phe233del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
PURA
NM_005859.5 conservative_inframe_deletion
NM_005859.5 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.00
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_005859.5. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 5-140114870-GCTT-G is Pathogenic according to our data. Variant chr5-140114870-GCTT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-140114870-GCTT-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PURA | NM_005859.5 | c.697_699delTTC | p.Phe233del | conservative_inframe_deletion | 1/1 | ENST00000331327.5 | NP_005850.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PURA | ENST00000331327.5 | c.697_699delTTC | p.Phe233del | conservative_inframe_deletion | 1/1 | 6 | NM_005859.5 | ENSP00000332706.3 | ||
PURA | ENST00000651386.1 | c.697_699delTTC | p.Phe233del | conservative_inframe_deletion | 2/2 | ENSP00000499133.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:15Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome Pathogenic:9Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | A Heterozygous Inframe indel variant c.690_692delCTT in Exon 1 of the PURA gene that results in the amino acid substitution p.Phe231del was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic (ClinVar ID: 189319). The Phe233del variant in PURA has been reported in 8 patients with autosomal dominat PURA syndrome, characterized by moderate to severe intellectual disability (ID) and several early-onset issues including motor delay, hypotonia, feeding difficulties, hyperthermia, hypersomnolence, hypoventilation/apneas, speech delay and abnormal nonepileptic movements. p.Phe233del falls in the third PUR domain that mediate dimerization, and is predicted to cause local folding defects (Reijnders MRF et al., 2018 and Hunt D et al., 2014). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Department, Johns Hopkins All Children's Hospital | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region was predicted to change the length of the protein and disrupt normal protein function. The variant has been previously reported as de novo in similarly affected individuals (PMID: 25342064 ‚PMID: 29150892 ‚PMID: 29097605 ‚ PMID: 28726809, PMID: 27148565). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 27, 2019 | Variant summary: PURA c.697_699delTTC (p.Phe233del) results in an in-frame deletion that is predicted to remove the third Phenylalanine in a run of three Phenylalanines located in the "presumed functional domain of PURA which is necessary for homodimerisation in crystallography studies (Hunt_2014). " The variant was absent in 251468 control chromosomes (gnomAD). c.697_699delTTC has been reported in the literature in multiple individuals affected with mental retardation and delays in cognitive development (Hunt_2014, Tanaka_2015, Strauss_2017, Lee_2018, Reijnders_2018). All the patients presented the mutation as a de novo occurrence. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Division of Biology and Genetics, University of Brescia | - | The Phe233del variant in PURA has been reported in 8 patients with autosomal dominat PURA syndrome, characterized by moderate to severe intellectual disability (ID) and several early-onset issues including motor delay, hypotonia, feeding difficulties, hyperthermia, hypersomnolence, hypoventilation/apneas, speech delay and abnormal nonepileptic movements. Other less common manifestations include congenital heart defects, skeletal, urogenital, ophthalmological, gastrointestinal, and endocrine abnormalities; soft skin was also described as well as craniofacial dysmorphism (Reijnders et al., 1993; Hunt et al., 2014; Tanaka et al., 2015; Reijnders et al., 2018; Lee et al., 2018). p.Phe233del falls in the third PUR domain that mediate dimerization, and is predicted to cause local folding defects (Reijnders et al., 2018). Its putative pathogenicy was estimated through 3 different in silico prediction algorithms (SIFT, PROVEAN, MutPred Indel) that agreed to define p.phe233del as pathogenetic - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 28, 2022 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 16, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 189319). This variant has been observed in individual(s) with developmental delay, cortical visual impairment, and hypotonia (PMID: 25342064, 27148565). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.697_699del, results in the deletion of 1 amino acid(s) of the PURA protein (p.Phe233del), but otherwise preserves the integrity of the reading frame. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 11, 2022 | In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27148565, 25342064, 29150892, 28726809, 31028937, 29097605, 31273778, 33275834) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 24, 2017 | - - |
PURA Syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has been previously reported as a de novo change in patients with intellectual disability, motor and cognitive delays hypotonia, feeding difficulties and seizures (PMID: 27148565, 31273778, 25342064). The c.697_699del (p.Phe233del) variant affects a highly conserved phenylalanine residue in the PUR repeat III which has been implicated in the dimerization of two PURA molecules (PMID: 19846792). It is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. However, low-level parental mosaicism cannot be excluded. Based on the available evidence, the c.697_699del (p.Phe233del) variant is classified as Pathogenic. - |
PURA-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 08, 2023 | The PURA c.697_699delTTC variant is predicted to result in an in-frame deletion (p.Phe233del). This variant has been reported de novo in multiple individuals with PURA syndrome (Hunt et al. 2014. PubMed ID: 25342064; Tanaka et al. 2015. PubMed ID: 27148565; Strauss et al. 2018. PubMed ID: 28726809; Reijnders et al. 2018. PubMed ID: 29097605; Lee et al. 2018. PubMed ID: 29150892; Borlot et al. 2019. PubMed ID: 31273778; Cinquina et al. 2021. PubMed ID: 33275834). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at