1-15500641-C-T

Position:

• chr1-15500641-C-T

Variant summary

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

The NM_001229.5(CASP9):​c.868+3970G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 152,008 control chromosomes in the GnomAD database, including 6,699 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 0.28 (6699 hom., cov: 32)
• Consequence: CASP9 NM_001229.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.47

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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP9	NM_001229.5	c.868+3970G>A		intron_variant		ENST00000333868.10	NP_001220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP9	ENST00000333868.10	c.868+3970G>A		intron_variant		1	NM_001229.5	ENSP00000330237.5

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42033 AN: 151892 Hom.: 6670 Cov.: 32

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.187

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.0640

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.269

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

GnomAD4 genome AF: 0.277 AC: 42101 AN: 152008 Hom.: 6699 Cov.: 32 AF XY: 0.274 AC XY: 20372 AN XY: 74292

Gnomad4 AFR AF: 0.427

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.254

Gnomad4 EAS AF: 0.0641

Gnomad4 SAS AF: 0.180

Gnomad4 FIN AF: 0.282

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.267

Alfa AF: 0.243 Hom.: 591

Bravo AF: 0.276

Asia WGS AF: 0.162 AC: 562 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.025
DANN	Benign	0.42

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: rs4646077; hg19: chr1-15827136;