rs1057517786

Positions:

• chr3-167704889-G-A
• chr3-167704889-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007217.4(PDCD10):​c.103C>T​(p.Arg35*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PDCD10 NM_007217.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.12

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]

PDCD10 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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 3-167704889-G-A is Pathogenic according to our data. Variant chr3-167704889-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 372445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-167704889-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDCD10	NM_007217.4	c.103C>T	p.Arg35*	stop_gained	4/9	ENST00000392750.7	NP_009148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDCD10	ENST00000392750.7	c.103C>T	p.Arg35*	stop_gained	4/9	1	NM_007217.4	ENSP00000376506.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450956 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 722432

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26896283, 23485406, 30161288, 25354366, 31254430, 23595507, 35883785, 18035376, 15543491) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	PDCD10: PVS1, PM2, PS4:Moderate -

Cerebral cavernous malformation 3 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 07, 2023	This sequence change creates a premature translational stop signal (p.Arg35*) in the PDCD10 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PDCD10 are known to be pathogenic (PMID: 15543491, 18300272, 23801932). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cerebral cavernous malformations (PMID: 15543491, 18035376, 23485406, 23595507, 26896283). This variant is also known as 30075cga-TGA stop. ClinVar contains an entry for this variant (Variation ID: 372445). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 03, 2023	The PDCD10 c.103C>T; p.Arg35Ter variant (rs1057517786), also published as 30075cga-TGA stop, is reported in the literature in multiple individuals and families affected with cerebral cavernous malformations (Bergametti 2005, Bilo 2016, Fusco 2019, Lee 2008, Tsutsumi 2013). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Bergametti F et al. Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet. 2005 Jan;76(1):42-51. PMID: 15543491. Bilo L et al. CCM3/PDCD10 gene mutation in cerebral cavernous malformations associated with hyperkeratotic cutaneous capillary venous malformations. J Dermatol. 2016 Aug;43(8):962-3. PMID: 26896283. Fusco C et al. Molecular diagnostic workflow, clinical interpretation of sequence variants, and data repository procedures in 140 individuals with familial cerebral cavernous malformations. Hum Mutat. 2019 Nov;40(11):e24-e36. PMID: 31254430. Lee ST et al. Identification of an Arg35X mutation in the PDCD10 gene in a patient with cerebral and multiple spinal cavernous malformations. J Neurol Sci. 2008 Apr 15;267(1-2):177-81. PMID: 18035376. Tsutsumi S et al. Genomic causes of multiple cerebral cavernous malformations in a Japanese population. J Clin Neurosci. 2013 May;20(5):667-9. PMID: 23485406. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2005	- -

Cerebral cavernous malformation Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Medical Genetics, University of Torino

Oct 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.92	D
Vest4		0.91
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057517786; hg19: chr3-167422677;