rs577939683

Variant names:

• chr3-167713274-CAA-C
• rs577939683
• NM_007217.4:c.96+6786_96+6787delTT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_007217.4(PDCD10):​c.96+6786_96+6787delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00299 in 152,046 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: 𝑓 0.0030 (2 hom., cov: 32)
• Consequence: PDCD10 NM_007217.4 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.303
• 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 -5 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00299 (454/152046) while in subpopulation AMR AF = 0.00504 (77/15272). AF 95% confidence interval is 0.00429. There are 2 homozygotes in GnomAd4. There are 210 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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 454 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDCD10	NM_007217.4	c.96+6786_96+6787delTT		intron_variant	Intron 3 of 8	ENST00000392750.7	NP_009148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDCD10	ENST00000392750.7	c.96+6786_96+6787delTT		intron_variant	Intron 3 of 8	1	NM_007217.4	ENSP00000376506.2

Frequencies

GnomAD3 genomes AF: 0.00299 AC: 454 AN: 151930 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00505

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00472

Gnomad OTH AF: 0.00336

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00299 AC: 454 AN: 152046 Hom.: 2 Cov.: 32 AF XY: 0.00283 AC XY: 210 AN XY: 74336

African (AFR) AF: 0.000578 AC: 24 AN: 41534

American (AMR) AF: 0.00504 AC: 77 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4822

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00472 AC: 320 AN: 67844

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.00314

Asia WGS AF: 0.00116 AC: 4 AN: 3474

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Cerebral cavernous malformation 3 Other:1

May 15, 2017

Institute of Human Genetics Greifswald, Research Division, University Medicine Greifswald

Significance: not provided

Review Status: no classification provided

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.30

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: rs577939683; hg19: chr3-167431062;