5-140114195-ACAGCGGCAGCG-C

Variant names:

• chr5-140114195-ACAGCGGCAGCG-C
• rs1554129000
• NM_005859.5:c.14_25delACAGCGGCAGCGinsC

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PM2 PP2 PP5_Moderate

The NM_005859.5(PURA):​c.14_25delACAGCGGCAGCGinsC​(p.Asp5AlafsTer192) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PURA NM_005859.5 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.93

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 13 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 22 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PURA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 3.3704 (above the threshold of 3.09). Trascript score misZ: 4.4395 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 40, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutation, complex neurodevelopmental disorder.
• PP5: Variant 5-140114195-ACAGCGGCAGCG-C is Pathogenic according to our data. Variant chr5-140114195-ACAGCGGCAGCG-C is described in ClinVar as [Pathogenic]. Clinvar id is 452213.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PURA	NM_005859.5	c.14_25delACAGCGGCAGCGinsC	p.Asp5AlafsTer192	frameshift_variant, missense_variant	Exon 1 of 1	ENST00000331327.5	NP_005850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PURA	ENST00000331327.5	c.14_25delACAGCGGCAGCGinsC	p.Asp5AlafsTer192	frameshift_variant, missense_variant	Exon 1 of 1	6	NM_005859.5	ENSP00000332706.3
PURA	ENST00000651386.1	c.14_25delACAGCGGCAGCGinsC	p.Asp5AlafsTer192	frameshift_variant, missense_variant	Exon 2 of 2			ENSP00000499133.1
PURA	ENST00000505703.2	c.14_25delACAGCGGCAGCGinsC	p.Asp5AlafsTer98	frameshift_variant, missense_variant	Exon 2 of 2	3		ENSP00000498560.1
PURA	ENST00000502351.1	c.14_25delACAGCGGCAGCGinsC	p.Asp5AlafsTer18	frameshift_variant, missense_variant	Exon 2 of 2	2		ENSP00000498760.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Sep 13, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14_25del12insC variant in the PURA gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant causes a frameshift starting with codon Aspartic acid 5, changes this amino acid to an Alanine residue, and creates a premature Stop codon at position 192 of the new reading frame, denoted p.Asp5AlafsX192. This variant is predicted to cause loss of normal protein function through protein truncation. Although no data are available from control populations to assess the frequency of this variant, we interpret c.14_25del12insC as a pathogenic variant. -

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: rs1554129000; hg19: chr5-139493780;