rs786204835

chr5-140114870-GCTT-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_005859.5(PURA):c.697_699del(p.Phe233del) variant causes a 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 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• 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]

ACMG classification

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	UniProt
PURA	NM_005859.5	c.697_699del	p.Phe233del	inframe_deletion	1/1	ENST00000331327.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PURA	ENST00000331327.5	c.697_699del	p.Phe233del	inframe_deletion	1/1		NM_005859.5	P1
PURA	ENST00000651386.1	c.697_699del	p.Phe233del	inframe_deletion	2/2			P1

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/Likely pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome Pathogenic:9 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 28, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2014	- -
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	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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
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, criteria provided, single submitter	clinical testing	Invitae	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. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Department, Johns Hopkins All Children's Hospital	-	- -
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. -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
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) -

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, criteria provided, single submitter

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

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: rs786204835; hg19: chr5-139494455;