5-140114295-GGGCGGCGGCGGCAGTGGCGGCGGCGGC-GGGC

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_005859.5(PURA):c.123_146del(p.Gly42_Gly49del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000534 in 1,254,568 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G39G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: PURA NM_005859.5 inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.66

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 Benign. Variant got -12 ACMG points.

• BP6: Variant 5-140114295-GGGCGGCGGCGGCAGTGGCGGCGGC-G is Benign according to our data. Variant chr5-140114295-GGGCGGCGGCGGCAGTGGCGGCGGC-G is described in ClinVar as [Likely_benign]. Clinvar id is 475284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PURA	NM_005859.5	c.123_146del	p.Gly42_Gly49del	inframe_deletion	1/1	ENST00000331327.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PURA	ENST00000331327.5	c.123_146del	p.Gly42_Gly49del	inframe_deletion	1/1		NM_005859.5	P1
PURA	ENST00000505703.2	c.123_146del	p.Gly42_Gly49del	inframe_deletion	2/2	3
PURA	ENST00000651386.1	c.123_146del	p.Gly42_Gly49del	inframe_deletion	2/2			P1
PURA	ENST00000502351.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000402 AC: 6 AN: 149126 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000898

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000560 AC: 4 AN: 7138 Hom.: 0 AF XY: 0.000659 AC XY: 3 AN XY: 4552

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000540

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000552 AC: 61 AN: 1105442 Hom.: 0 AF XY: 0.0000621 AC XY: 33 AN XY: 531434

Gnomad4 AFR exome AF: 0.0000882

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000574

Gnomad4 OTH exome AF: 0.0000226

GnomAD4 genome AF: 0.0000402 AC: 6 AN: 149126 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 2 AN XY: 72718

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000898

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PURA p.Gly42_Gly49del variant was not identified in the literature but was identified in dbSNP (ID: rs1014354489) and ClinVar (classified as likely benign by Invitae). The variant was identified in control databases in 5 of 35864 chromosomes at a frequency of 0.0001394 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 2 of 1530 chromosomes (freq: 0.001307) and European (non-Finnish) in 3 of 18170 chromosomes (freq: 0.000165), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. This is greater than the expected frequency for the severe, early-onset autosomal dominant PURA-Related Neurodevelopmental Disorders. This variant is an in-frame deletion resulting in the removal of glycine (gly) residues from codon 42 to 49; the impact of this alteration on PURA protein function is not known however this occurs within a glycine repeat region. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2018	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs750397204; hg19: chr5-139493880;