5-140114334-AG-AGG

Variant names:

• chr5-140114334-A-AG
• rs1554129040
• NM_005859.5:c.159dupG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005859.5(PURA):​c.159dupG​(p.Leu54AlafsTer147) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000777 in 1,287,560 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L54L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: PURA NM_005859.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 1.70
• Publications: 1 publications found

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]

MALINC1 (HGNC:49009): (mitosis associated long intergenic non-coding RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 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 173 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-140114334-A-AG is Pathogenic according to our data. Variant chr5-140114334-A-AG is described in ClinVar as Pathogenic. ClinVar VariationId is 432233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005859.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PURA	NM_005859.5	MANE Select	c.159dupG	p.Leu54AlafsTer147	frameshift	Exon 1 of 1	NP_005850.1	Q00577

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PURA	ENST00000331327.5	TSL:6 MANE Select	c.159dupG	p.Leu54AlafsTer147	frameshift	Exon 1 of 1	ENSP00000332706.3	Q00577
	PURA	ENST00000651386.1		c.159dupG	p.Leu54AlafsTer147	frameshift	Exon 2 of 2	ENSP00000499133.1	Q00577
	PURA	ENST00000505703.2	TSL:3	c.159dupG	p.Leu54AlafsTer53	frameshift	Exon 2 of 2	ENSP00000498560.1	A0A494C0H6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.77e-7 AC: 1 AN: 1287560 Hom.: 0 Cov.: 33 AF XY: 0.00000157 AC XY: 1 AN XY: 636982

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27480

American (AMR) AF: 0.00 AC: 0 AN: 28324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30124

South Asian (SAS) AF: 0.00 AC: 0 AN: 62320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4428

European-Non Finnish (NFE) AF: 9.71e-7 AC: 1 AN: 1029580

Other (OTH) AF: 0.00 AC: 0 AN: 52308

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome (5)
3	-	-	not provided (3)
1	-	-	Intellectual disability (1)
1	-	-	PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554129040; hg19: chr5-139493919;