chr5-140114184-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_005859.5(PURA):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000157 in 636,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. MADRDSGSEQGGAALGSGGSLGHPGSGSGSGGGGGGGGGGGGSGGGGGGAPGGLQHETQELASKRVDIQNKRFYLDVKQNAKGRFLKI1?) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

PURA
NM_005859.5 start_lost

Scores

4
5
7

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.44
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 14 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_005859.5 (PURA) was described as [Likely_pathogenic] in ClinVar as 489294
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-140114184-G-A is Pathogenic according to our data. Variant chr5-140114184-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2098281.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PURANM_005859.5 linkuse as main transcriptc.3G>A p.Met1? start_lost 1/1 ENST00000331327.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PURAENST00000331327.5 linkuse as main transcriptc.3G>A p.Met1? start_lost 1/1 NM_005859.5 P1
PURAENST00000651386.1 linkuse as main transcriptc.3G>A p.Met1? start_lost 2/2 P1
PURAENST00000505703.2 linkuse as main transcriptc.3G>A p.Met1? start_lost 2/23
PURAENST00000502351.1 linkuse as main transcriptc.3G>A p.Met1? start_lost 2/22

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000157
AC:
1
AN:
636866
Hom.:
0
Cov.:
9
AF XY:
0.00000323
AC XY:
1
AN XY:
309904
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000190
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeMay 17, 2022This sequence change affects the initiator methionine of the PURA mRNA. The next in-frame methionine is located at codon 104. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with clinical features of PURA syndrome (PMID: 27148565, 32337850). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Uncertain
0.060
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.38
T
Eigen
Benign
-0.035
Eigen_PC
Benign
0.034
FATHMM_MKL
Benign
0.63
D
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Benign
-0.92
T
MutationTaster
Benign
1.0
D
PROVEAN
Benign
-0.71
N
REVEL
Uncertain
0.30
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.034
D
Polyphen
0.27
B
Vest4
0.68
MutPred
0.99
Gain of catalytic residue at M1 (P = 0.1346);
MVP
0.83
ClinPred
1.0
D
GERP RS
3.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.88
gMVP
0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-139493769; API