rs884363

Positions:

• chr1-15493273-C-A
• chr1-15493273-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000333868.10(CASP9):​c.1159-238G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.572 in 1,379,242 control chromosomes in the GnomAD database, including 230,435 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.64 (33085 hom., cov: 33)
  • Exomes 𝑓: 0.56 (197350 hom.)
• Consequence: CASP9 ENST00000333868.10 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.787

Genes affected

CASP9 (HGNC:1511): (caspase 9) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein can undergo autoproteolytic processing and activation by the apoptosome, a protein complex of cytochrome c and the apoptotic peptidase activating factor 1; this step is thought to be one of the earliest in the caspase activation cascade. This protein is thought to play a central role in apoptosis and to be a tumor suppressor. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP9	NM_001229.5	c.1159-238G>T		intron_variant		ENST00000333868.10	NP_001220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP9	ENST00000333868.10	c.1159-238G>T		intron_variant		1	NM_001229.5	ENSP00000330237	P1

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97925 AN: 152034 Hom.: 33039 Cov.: 33

Gnomad AFR AF: 0.851

Gnomad AMI AF: 0.645

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.647

Gnomad SAS AF: 0.433

Gnomad FIN AF: 0.673

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.595

GnomAD4 exome AF: 0.563 AC: 691188 AN: 1227090 Hom.: 197350 Cov.: 34 AF XY: 0.560 AC XY: 331943 AN XY: 592242

Gnomad4 AFR exome AF: 0.860

Gnomad4 AMR exome AF: 0.481

Gnomad4 ASJ exome AF: 0.514

Gnomad4 EAS exome AF: 0.650

Gnomad4 SAS exome AF: 0.447

Gnomad4 FIN exome AF: 0.661

Gnomad4 NFE exome AF: 0.558

Gnomad4 OTH exome AF: 0.570

GnomAD4 genome AF: 0.644 AC: 98020 AN: 152152 Hom.: 33085 Cov.: 33 AF XY: 0.644 AC XY: 47884 AN XY: 74392

Gnomad4 AFR AF: 0.852

Gnomad4 AMR AF: 0.528

Gnomad4 ASJ AF: 0.511

Gnomad4 EAS AF: 0.647

Gnomad4 SAS AF: 0.431

Gnomad4 FIN AF: 0.673

Gnomad4 NFE AF: 0.563

Gnomad4 OTH AF: 0.591

Alfa AF: 0.607 Hom.: 3580

Bravo AF: 0.643

Asia WGS AF: 0.568 AC: 1973 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.22
DANN	Benign	0.39

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: rs884363; hg19: chr1-15819768;