rs3792293

Variant names:

• chr3-167734716-A-G
• rs3792293
• NM_007217.4:c.-308T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007217.4(PDCD10):​c.-308T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 154,570 control chromosomes in the GnomAD database, including 7,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7355 hom., cov: 33)
  • Exomes 𝑓: 0.26 (96 hom.)
• Consequence: PDCD10 NM_007217.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.18
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-167734716-A-G is Benign according to our data. Variant chr3-167734716-A-G is described in ClinVar as Benign. ClinVar VariationId is 590668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

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.-308T>C		5_prime_UTR	Exon 1 of 9	NP_009148.2
	PDCD10	NM_001439202.1		c.-249+90T>C		intron	N/A	NP_001426131.1
	PDCD10	NM_145859.2		c.-190+90T>C		intron	N/A	NP_665858.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDCD10	ENST00000392750.7	TSL:1 MANE Select	c.-308T>C		5_prime_UTR	Exon 1 of 9	ENSP00000376506.2
	PDCD10	ENST00000473645.6	TSL:1	c.-190+90T>C		intron	N/A	ENSP00000418317.2
	PDCD10	ENST00000497056.6	TSL:1	c.-117+90T>C		intron	N/A	ENSP00000420553.2

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45593 AN: 152128 Hom.: 7339 Cov.: 33

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.256

GnomAD4 exome AF: 0.257 AC: 597 AN: 2324 Hom.: 96 Cov.: 0 AF XY: 0.254 AC XY: 427 AN XY: 1684

African (AFR) AF: 0.333 AC: 8 AN: 24

American (AMR) AF: 0.357 AC: 10 AN: 28

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12

East Asian (EAS) AF: 0.203 AC: 13 AN: 64

South Asian (SAS) AF: 0.184 AC: 7 AN: 38

European-Finnish (FIN) AF: 0.324 AC: 140 AN: 432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 16

European-Non Finnish (NFE) AF: 0.242 AC: 393 AN: 1626

Other (OTH) AF: 0.310 AC: 26 AN: 84

GnomAD4 genome AF: 0.300 AC: 45640 AN: 152246 Hom.: 7355 Cov.: 33 AF XY: 0.297 AC XY: 22084 AN XY: 74430

African (AFR) AF: 0.426 AC: 17687 AN: 41538

American (AMR) AF: 0.186 AC: 2853 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 557 AN: 3472

East Asian (EAS) AF: 0.302 AC: 1558 AN: 5162

South Asian (SAS) AF: 0.126 AC: 607 AN: 4832

European-Finnish (FIN) AF: 0.317 AC: 3359 AN: 10604

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.268 AC: 18260 AN: 68016

Other (OTH) AF: 0.257 AC: 543 AN: 2114

Alfa AF: 0.273 Hom.: 20538

Bravo AF: 0.295

Asia WGS AF: 0.223 AC: 776 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 17, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Apr 02, 2018

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.3
DANN	Benign	0.64
PhyloP100		-1.2
PromoterAI		0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3792293; hg19: chr3-167452504; COSMIC: COSV55507798; COSMIC: COSV55507798;