rs4645981

Positions:

• chr1-15524988-G-A
• chr1-15524988-G-C

Variant summary

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

The ENST00000469637.1(CASP9):​c.-239+1203C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00823 in 105,452 control chromosomes in the GnomAD database, including 41 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 0.0083 (41 hom., cov: 21)
  • Exomes 𝑓: 0.0022 (0 hom.)
• Consequence: CASP9 ENST00000469637.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.154

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=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP9	ENST00000469637.1	c.-239+1203C>T		intron_variant		3		ENSP00000480785.1

Frequencies

GnomAD3 genomes AF: 0.00834 AC: 864 AN: 103580 Hom.: 41 Cov.: 21

Gnomad AFR AF: 0.000564

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.00558

Gnomad FIN AF: 0.0193

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000619

Gnomad OTH AF: 0.00797

GnomAD4 exome AF: 0.00218 AC: 4 AN: 1836 Hom.: 0 AF XY: 0.00347 AC XY: 4 AN XY: 1154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00509

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00834 AC: 864 AN: 103616 Hom.: 41 Cov.: 21 AF XY: 0.00966 AC XY: 464 AN XY: 48056

Gnomad4 AFR AF: 0.000563

Gnomad4 AMR AF: 0.0201

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.164

Gnomad4 SAS AF: 0.00632

Gnomad4 FIN AF: 0.0193

Gnomad4 NFE AF: 0.000619

Gnomad4 OTH AF: 0.00795

Alfa AF: 0.00293 Hom.: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.4
DANN	Benign	0.63

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4645981; hg19: chr1-15851483;