5-140114183-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_005859.5(PURA):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-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 (★). Synonymous variant affecting the same amino acid position (i.e. MADRDSGSEQGGAALGSGGSLGHPGSGSGSGGGGGGGGGGGGSGGGGGGAPGGLQHETQELASKRVDIQNKRFYLDVKQNAKGRFLKI1?) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PURA NM_005859.5 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.83

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 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 5-140114183-T-C is Pathogenic according to our data. Variant chr5-140114183-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2807849.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PURA	NM_005859.5	c.2T>C	p.Met1?	start_lost	1/1	ENST00000331327.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PURA	ENST00000331327.5	c.2T>C	p.Met1?	start_lost	1/1		NM_005859.5	P1
PURA	ENST00000651386.1	c.2T>C	p.Met1?	start_lost	2/2			P1
PURA	ENST00000505703.2	c.2T>C	p.Met1?	start_lost	2/2	3
PURA	ENST00000502351.1	c.2T>C	p.Met1?	start_lost	2/2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 606046 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 295768

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 07, 2022

For 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	Benign	-0.16
Cadd	Uncertain	24
Dann	Benign	0.97
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.042
Eigen_PC	Benign	-0.0042
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.46	P
Vest4		0.63
MutPred		0.97		Gain of phosphorylation at M1 (P = 0.0013);
MVP		0.47
ClinPred		0.99	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.81
gMVP		0.53

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: chr5-139493768;