5-140114482-A-ACT

Position:

• chr5-140114482-A-ACT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_005859.5(PURA):​c.307_308dupTC​(p.Met104fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PURA NM_005859.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.98

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 Likely_pathogenic. Variant got 8 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 17 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-140114482-A-ACT is Pathogenic according to our data. Variant chr5-140114482-A-ACT is described in ClinVar as [Pathogenic]. Clinvar id is 419325.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PURA	NM_005859.5	c.307_308dupTC	p.Met104fs	frameshift_variant	1/1	ENST00000331327.5	NP_005850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PURA	ENST00000331327.5	c.307_308dupTC	p.Met104fs	frameshift_variant	1/1	6	NM_005859.5	ENSP00000332706.3
PURA	ENST00000651386.1	c.307_308dupTC	p.Met104fs	frameshift_variant	2/2			ENSP00000499133.1
PURA	ENST00000505703.2	c.307_308dupTC	p.Met104fs	frameshift_variant	2/2	3		ENSP00000498560.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2015

The c.307_308dupTC duplication in the PURA gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. The c.307_308dupTC duplication causes aframeshift starting with codon Methionine 104, changes this amino acid to a Proline residue, and creates apremature Stop codon at position 122 of the new reading frame, denoted p.Met104ProfsX122. Thisduplication is predicted to cause loss of normal protein function through protein truncation. Thec.307_308dupTC variant was not observed in approximately 6500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variantin these populations. We interpret c.307_308dupTC 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: rs587782992; hg19: chr5-139494067;