rs1057517786

Variant names:

• chr3-167704889-G-A
• rs1057517786
• NM_007217.4:c.103C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 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. 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
• Publications: 5 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 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 VariationId is 372445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007217.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDCD10	NM_007217.4	MANE Select	c.103C>T	p.Arg35*	stop_gained	Exon 4 of 9	NP_009148.2
	PDCD10	NM_001439202.1		c.103C>T	p.Arg35*	stop_gained	Exon 4 of 9	NP_001426131.1
	PDCD10	NM_001439204.1		c.103C>T	p.Arg35*	stop_gained	Exon 3 of 8	NP_001426133.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDCD10	ENST00000392750.7	TSL:1 MANE Select	c.103C>T	p.Arg35*	stop_gained	Exon 4 of 9	ENSP00000376506.2
	PDCD10	ENST00000473645.6	TSL:1	c.103C>T	p.Arg35*	stop_gained	Exon 4 of 9	ENSP00000418317.2
	PDCD10	ENST00000497056.6	TSL:1	c.103C>T	p.Arg35*	stop_gained	Exon 3 of 8	ENSP00000420553.2

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

African (AFR) AF: 0.00 AC: 0 AN: 33248

American (AMR) AF: 0.00 AC: 0 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 85864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102938

Other (OTH) AF: 0.00 AC: 0 AN: 59988

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Cerebral cavernous malformation 3 (3)
3	-	-	not provided (3)
1	-	-	Cerebral cavernous malformation (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.1
Vest4		0.91
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs1057517786; hg19: chr3-167422677;