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rs587782994

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_005859.5(PURA):​c.289A>G​(p.Lys97Glu) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

PURA
NM_005859.5 missense

Scores

9
8
2

Clinical Significance

Pathogenic no assertion criteria provided P:2O:1

Conservation

PhyloP100: 7.27
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 10 ACMG points.

PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 3 uncertain in NM_005859.5
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP2
?
    PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, PURA
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.946
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 5-140114470-A-G is Pathogenic according to our data. Variant chr5-140114470-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 156406.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PURANM_005859.5 linkuse as main transcriptc.289A>G p.Lys97Glu missense_variant 1/1 ENST00000331327.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PURAENST00000331327.5 linkuse as main transcriptc.289A>G p.Lys97Glu missense_variant 1/1 NM_005859.5 P1
PURAENST00000651386.1 linkuse as main transcriptc.289A>G p.Lys97Glu missense_variant 2/2 P1
PURAENST00000505703.2 linkuse as main transcriptc.289A>G p.Lys97Glu missense_variant 2/23

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome Pathogenic:1Other:1
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 06, 2014- -
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
0.27
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.86
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Benign
-0.51
T
MutationAssessor
Uncertain
2.1
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.75
T
PROVEAN
Uncertain
-3.2
D
REVEL
Pathogenic
0.89
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.017
D
Polyphen
1.0
D
Vest4
0.90
MutPred
0.71
Loss of ubiquitination at K97 (P = 0.0174);
MVP
0.68
MPC
3.3
ClinPred
0.99
D
GERP RS
4.7
Varity_R
0.79
gMVP
0.99

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: rs587782994; hg19: chr5-139494055; API