Genetic Variant PDCD10:c.*339G>A (chr3-167683969-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_007217.4(PDCD10):c.*339G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.000412 in 240,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

PDCD10
NM_007217.4 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.97

Publications

1 publications found

Variant links:

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

PDCD10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.17).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000423 (64/151378) while in subpopulation NFE AF = 0.000708 (48/67824). AF 95% confidence interval is 0.000548. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 64 AD gene.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PDCD10	NM_007217.4	MANE Select	c.*339G>A	3_prime_UTR	Exon 9 of 9	NP_009148.2
PDCD10	NM_001439202.1		c.*339G>A	3_prime_UTR	Exon 9 of 9	NP_001426131.1
PDCD10	NM_001439204.1		c.*339G>A	3_prime_UTR	Exon 8 of 8	NP_001426133.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PDCD10	ENST00000392750.7	TSL:1 MANE Select	c.*339G>A	3_prime_UTR	Exon 9 of 9	ENSP00000376506.2	Q9BUL8
PDCD10	ENST00000473645.6	TSL:1	c.*339G>A	3_prime_UTR	Exon 9 of 9	ENSP00000418317.2	Q9BUL8
PDCD10	ENST00000497056.6	TSL:1	c.*339G>A	3_prime_UTR	Exon 8 of 8	ENSP00000420553.2	Q9BUL8

Frequencies

GnomAD3 genomes

AF:

0.000423

AC:

AN:

151378

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000727

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000396

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000708

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000394

AC:

AN:

88786

Hom.:

Cov.:

AF XY:

0.000339

AC XY:

AN XY:

47212

show subpopulations

African (AFR)

AF:

0.000348

AC:

AN:

2874

American (AMR)

AF:

0.00109

AC:

AN:

4572

Ashkenazi Jewish (ASJ)

AF:

0.000482

AC:

AN:

2074

East Asian (EAS)

AF:

0.00

AC:

AN:

5296

South Asian (SAS)

AF:

0.00

AC:

AN:

14068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000511

AC:

AN:

50906

Other (OTH)

AF:

0.000437

AC:

AN:

4580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000423

AC:

AN:

151378

Hom.:

Cov.:

AF XY:

0.000366

AC XY:

AN XY:

73858

show subpopulations

African (AFR)

AF:

0.0000727

AC:

AN:

41256

American (AMR)

AF:

0.000396

AC:

AN:

15166

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000708

AC:

AN:

67824

Other (OTH)

AF:

0.00

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000900

Hom.:

Bravo

AF:

0.000616

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cerebral cavernous malformation 3 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over