NM_007217.4:c.160_163delGAAA

Variant names:

• chr3-167697113-TTTTC-T
• rs1553761266
• NM_007217.4:c.160_163delGAAA

Variant summary

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

The NM_007217.4(PDCD10):​c.160_163delGAAA​(p.Glu54IlefsTer10) 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDCD10 NM_007217.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.67
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• cerebral cavernous malformation 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• famililal cerebral cavernous malformations

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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 3-167697113-TTTTC-T is Pathogenic according to our data. Variant chr3-167697113-TTTTC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 468328.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDCD10	NM_007217.4	c.160_163delGAAA	p.Glu54IlefsTer10	frameshift_variant	Exon 5 of 9	ENST00000392750.7	NP_009148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDCD10	ENST00000392750.7	c.160_163delGAAA	p.Glu54IlefsTer10	frameshift_variant	Exon 5 of 9	1	NM_007217.4	ENSP00000376506.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cerebral cavernous malformation 3 Pathogenic:1

Aug 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 468328). This variant has not been reported in the literature in individuals affected with PDCD10-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu54Ilefs*10) 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1553761266; hg19: chr3-167414901;