5-140114184-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_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 (★).

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 6 pathogenic variants. Next in-frame start position is after 309 CDS bases. Genomic position: 140114490. Lost 0.319 part of the original CDS.
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 rank MANE Protein UniProt
PURANM_005859.5 linkc.3G>A p.Met1? start_lost Exon 1 of 1 ENST00000331327.5 NP_005850.1 Q00577

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PURAENST00000331327.5 linkc.3G>A p.Met1? start_lost Exon 1 of 1 6 NM_005859.5 ENSP00000332706.3 Q00577
PURAENST00000651386.1 linkc.3G>A p.Met1? start_lost Exon 2 of 2 ENSP00000499133.1 Q00577
PURAENST00000505703.2 linkc.3G>A p.Met1? start_lost Exon 2 of 2 3 ENSP00000498560.1 A0A494C0H6
PURAENST00000502351.1 linkc.3G>A p.Met1? start_lost Exon 2 of 2 2 ENSP00000498760.1 A0A494C0X8

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 testingLabcorp Genetics (formerly Invitae), LabcorpMay 17, 2022For these reasons, this variant has been classified as Pathogenic. 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. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the PURA mRNA. The next in-frame methionine is located at codon 104. -

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
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