5-140114191-C-T

Position:

• chr5-140114191-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005859.5(PURA):​c.10C>T​(p.Arg4Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000292 in 685,826 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: 0.0000029 (0 hom.)
• Consequence: PURA NM_005859.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.577

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 23 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-140114191-C-T is Pathogenic according to our data. Variant chr5-140114191-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 571407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-140114191-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PURA	NM_005859.5	c.10C>T	p.Arg4Ter	stop_gained	1/1	ENST00000331327.5	NP_005850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PURA	ENST00000331327.5	c.10C>T	p.Arg4Ter	stop_gained	1/1		NM_005859.5	ENSP00000332706	P1
PURA	ENST00000651386.1	c.10C>T	p.Arg4Ter	stop_gained	2/2			ENSP00000499133	P1
PURA	ENST00000505703.2	c.10C>T	p.Arg4Ter	stop_gained	2/2	3		ENSP00000498560
PURA	ENST00000502351.1	c.10C>T	p.Arg4Ter	stop_gained	2/2	2		ENSP00000498760

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000292 AC: 2 AN: 685826 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 332688

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: 0.00000349

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PURA protein in which other variant(s) (p.Tyr261*) have been determined to be pathogenic (PMID: 25439098). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 571407). This premature translational stop signal has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg4*) in the PURA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 319 amino acid(s) of the PURA protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 15, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 04, 2024

Nonsense variant predicted to result in protein truncation, as the last 319 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34070668, 31440721, 36376392) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.35	N
MutationTaster	Benign	1.0	D
Vest4		0.59
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs1561792945; hg19: chr5-139493776;