chr3-167684380-ATT-A
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_007217.4(PDCD10):c.565_566del(p.Asn189CysfsTer39) 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
NM_007217.4 frameshift
NM_007217.4 frameshift
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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. Fraction of 0.116 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-167684380-ATT-A is Pathogenic according to our data. Variant chr3-167684380-ATT-A is described in ClinVar as [Pathogenic]. Clinvar id is 964266.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.565_566del | p.Asn189CysfsTer39 | 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.565_566del | p.Asn189CysfsTer39 | frameshift_variant | 9/9 | 1 | NM_007217.4 | ENSP00000376506 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cerebral cavernous malformation 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 04, 2019 | This sequence change results in a frameshift in the PDCD10 gene (p.Asn189Cysfs*39). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acids of the PDCD10 protein and extend the protein by an additional 14 amino acids. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PDCD10-related conditions. 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. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at