rs587783001

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_005859.5(PURA):​c.596G>C​(p.Arg199Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

PURA
NM_005859.5 missense

Scores

14
3
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 9.95
Variant links:
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 15 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PURA. . Gene score misZ 3.3704 (greater than the threshold 3.09). Trascript score misZ 4.4395 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutation, complex neurodevelopmental disorder.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.96
PP5
Variant 5-140114777-G-C is Pathogenic according to our data. Variant chr5-140114777-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 156413.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
PURANM_005859.5 linkuse as main transcriptc.596G>C p.Arg199Pro missense_variant 1/1 ENST00000331327.5 NP_005850.1 Q00577

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PURAENST00000331327.5 linkuse as main transcriptc.596G>C p.Arg199Pro missense_variant 1/16 NM_005859.5 ENSP00000332706.3 Q00577
PURAENST00000651386.1 linkuse as main transcriptc.596G>C p.Arg199Pro missense_variant 2/2 ENSP00000499133.1 Q00577

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 29, 2020Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29150892, 25439098) -
Pathogenic, criteria provided, single submitterclinical testingLaboratoire de Génétique Moléculaire, CHU Bordeaux-- -
PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome Pathogenic:1Other:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 15, 2017In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported to be de novo an individual affected with seizures, hypotonia and feeding difficulties (PMID: 25439098). ClinVar contains an entry for this variant (Variation ID: 156413). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 199 of the PURA protein (p.Arg199Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. -
not provided, no classification providedliterature onlyGeneReviews-- -
Seizure;C0454644:Delayed speech and language development;C0557874:Global developmental delay;C2267233:Neonatal hypotonia;C3714756:Intellectual disability Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingWhole genome laboratory; Baylor College of MedicineSep 15, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
35
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
D
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.39
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Benign
-0.53
T
MutationAssessor
Pathogenic
3.2
M
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-6.5
D
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0030
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.93
MutPred
0.80
Loss of helix (P = 0.028);
MVP
0.82
MPC
4.1
ClinPred
1.0
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.95
gMVP
1.0

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587783001; hg19: chr5-139494362; API