3-167683969-C-T

Position:

• chr3-167683969-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

The ENST00000392750.7(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 ENST00000392750.7 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.97

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDCD10	NM_007217.4	c.*339G>A		3_prime_UTR_variant	9/9	ENST00000392750.7	NP_009148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDCD10	ENST00000392750.7	c.*339G>A		3_prime_UTR_variant	9/9	1	NM_007217.4	ENSP00000376506	P1
PDCD10	ENST00000473645.6	c.*339G>A		3_prime_UTR_variant	9/9	1		ENSP00000418317	P1
PDCD10	ENST00000497056.6	c.*339G>A		3_prime_UTR_variant	8/8	1		ENSP00000420553	P1

Frequencies

GnomAD3 genomes AF: 0.000423 AC: 64 AN: 151378 Hom.: 0 Cov.: 31

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: 35 AN: 88786 Hom.: 0 Cov.: 0 AF XY: 0.000339 AC XY: 16 AN XY: 47212

Gnomad4 AFR exome AF: 0.000348

Gnomad4 AMR exome AF: 0.00109

Gnomad4 ASJ exome AF: 0.000482

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000511

Gnomad4 OTH exome AF: 0.000437

GnomAD4 genome AF: 0.000423 AC: 64 AN: 151378 Hom.: 0 Cov.: 31 AF XY: 0.000366 AC XY: 27 AN XY: 73858

Gnomad4 AFR AF: 0.0000727

Gnomad4 AMR AF: 0.000396

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000708

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000900 Hom.: 0

Bravo AF: 0.000616

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Cerebral cavernous malformation 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	17
DANN	Benign	0.92
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

LitVar

Other links and lift over

dbSNP: rs528574350; hg19: chr3-167401757;