3-167684367-CACTT-C

Position:

• chr3-167684367-CACTT-C

Variant summary

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

The ENST00000392750.7(PDCD10):​c.576_579del​(p.Ser193ProfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. 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: PDCD10 ENST00000392750.7 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.52

Genes affected

PDCD10 (HGNC:8761): (programmed cell death 10) This gene encodes an evolutionarily conserved protein associated with cell apoptosis. The protein interacts with the serine/threonine protein kinase MST4 to modulate the extracellular signal-regulated kinase (ERK) pathway. It also interacts with and is phosphoryated by serine/threonine kinase 25, and is thought to function in a signaling pathway essential for vascular developent. Mutations in this gene are one cause of cerebral cavernous malformations, which are vascular malformations that cause seizures and cerebral hemorrhages. Multiple alternatively spliced variants, encoding the same protein, have been identified. [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 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-167684367-CACTT-C is Pathogenic according to our data. Variant chr3-167684367-CACTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 1075146.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDCD10	NM_007217.4	c.576_579del	p.Ser193ProfsTer4	frameshift_variant	9/9	ENST00000392750.7	NP_009148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDCD10	ENST00000392750.7	c.576_579del	p.Ser193ProfsTer4	frameshift_variant	9/9	1	NM_007217.4	ENSP00000376506	P1

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

Cerebral cavernous malformation 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 26, 2020

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the PDCD10 protein. Other variant(s) that disrupt this region (p.Arg196*) have been determined to be pathogenic (PMID: 15543491, 30161288). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with PDCD10-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the PDCD10 gene (p.Ser193Profs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 20 amino acids of the PDCD10 protein. -

Computational scores

Source: dbNSFP v4.3

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-167402155;