rs1553253812

Variant names:

• chr1-151025653-AG-A
• rs1553253812
• NM_021222.3:c.661delG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_021222.3(PRUNE1):​c.661delG​(p.Ala221GlnfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRUNE1 NM_021222.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.00700
• Publications: 0 publications found

Genes affected

PRUNE1 (HGNC:13420): (prune exopolyphosphatase 1) This gene encodes a member of the DHH protein superfamily of phosphoesterases. This protein has been found to function as both a nucleotide phosphodiesterase and an exopolyphosphatase. This protein is believed to stimulate cancer progression and metastases through the induction of cell motility. A pseuodgene has been identified on chromosome 13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

PRUNE1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-151025653-AG-A is Pathogenic according to our data. Variant chr1-151025653-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 521740.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021222.3. 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
	PRUNE1	NM_021222.3	MANE Select	c.661delG	p.Ala221GlnfsTer8	frameshift	Exon 5 of 8	NP_067045.1
	PRUNE1	NM_001303242.2		c.661delG	p.Ala221GlnfsTer8	frameshift	Exon 5 of 7	NP_001290171.1
	PRUNE1	NM_001303229.2		c.115delG	p.Ala39GlnfsTer8	frameshift	Exon 4 of 7	NP_001290158.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRUNE1	ENST00000271620.8	TSL:1 MANE Select	c.661delG	p.Ala221GlnfsTer8	frameshift	Exon 5 of 8	ENSP00000271620.3
	PRUNE1	ENST00000368936.5	TSL:1	c.115delG	p.Ala39GlnfsTer8	frameshift	Exon 4 of 7	ENSP00000357932.1
	PRUNE1	ENST00000368937.5	TSL:1	c.115delG	p.Ala39GlnfsTer8	frameshift	Exon 2 of 4	ENSP00000357933.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.0070
Mutation Taster		=0/200	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: rs1553253812; hg19: chr1-150998129;