rs1003688852

Variant names:

• chr3-167684360-C-T
• rs1003688852
• NM_007217.4:c.587G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-167684360-C-T
• chr3-167684360-C-A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_007217.4(PDCD10):​c.587G>A​(p.Arg196Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000056 in 1,606,536 control chromosomes in the GnomAD database, including 1 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000055 (1 hom.)
• Consequence: PDCD10 NM_007217.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.70
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28920746).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDCD10	NM_007217.4	MANE Select	c.587G>A	p.Arg196Gln	missense	Exon 9 of 9	NP_009148.2
	PDCD10	NM_001439202.1		c.587G>A	p.Arg196Gln	missense	Exon 9 of 9	NP_001426131.1
	PDCD10	NM_001439204.1		c.587G>A	p.Arg196Gln	missense	Exon 8 of 8	NP_001426133.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDCD10	ENST00000392750.7	TSL:1 MANE Select	c.587G>A	p.Arg196Gln	missense	Exon 9 of 9	ENSP00000376506.2	Q9BUL8
	PDCD10	ENST00000473645.6	TSL:1	c.587G>A	p.Arg196Gln	missense	Exon 9 of 9	ENSP00000418317.2	Q9BUL8
	PDCD10	ENST00000497056.6	TSL:1	c.587G>A	p.Arg196Gln	missense	Exon 8 of 8	ENSP00000420553.2	Q9BUL8

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151766 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1454770 Hom.: 1 Cov.: 27 AF XY: 0.00000828 AC XY: 6 AN XY: 724200

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33304

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39542

South Asian (SAS) AF: 0.00 AC: 0 AN: 86100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000543 AC: 6 AN: 1105902

Other (OTH) AF: 0.00 AC: 0 AN: 60096

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000227940), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151766 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74090

African (AFR) AF: 0.00 AC: 0 AN: 41298

American (AMR) AF: 0.0000657 AC: 1 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cerebral cavernous malformation 3 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.098	T
Eigen	Benign	0.074
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.86	L
PhyloP100		5.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.13
Sift	Benign	0.27	T
Sift4G	Benign	0.31	T
Polyphen		0.93	P
Vest4		0.48
MutPred		0.31		Loss of MoRF binding (P = 0.0547)
MVP		0.70
MPC		0.82
ClinPred		0.73	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.58
Mutation Taster		=67/33	polymorphism

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: rs1003688852; hg19: chr3-167402148;