rs4646047

Variant names:

• chr1-15505288-T-C
• rs4646047
• NM_001229.5:c.721-530A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001229.5(CASP9):​c.721-530A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 152,022 control chromosomes in the GnomAD database, including 26,835 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 0.59 (26835 hom., cov: 31)
• Consequence: CASP9 NM_001229.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.86
• Publications: 12 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.07).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP9	NM_001229.5	c.721-530A>G		intron_variant	Intron 5 of 8	ENST00000333868.10	NP_001220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP9	ENST00000333868.10	c.721-530A>G		intron_variant	Intron 5 of 8	1	NM_001229.5	ENSP00000330237.5

Frequencies

GnomAD3 genomes AF: 0.587 AC: 89100 AN: 151904 Hom.: 26795 Cov.: 31

Gnomad AFR AF: 0.705

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.647

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.650

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.557

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

GnomAD4 genome AF: 0.587 AC: 89188 AN: 152022 Hom.: 26835 Cov.: 31 AF XY: 0.587 AC XY: 43624 AN XY: 74300

African (AFR) AF: 0.706 AC: 29275 AN: 41480

American (AMR) AF: 0.498 AC: 7613 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 1714 AN: 3470

East Asian (EAS) AF: 0.647 AC: 3335 AN: 5158

South Asian (SAS) AF: 0.424 AC: 2044 AN: 4820

European-Finnish (FIN) AF: 0.650 AC: 6866 AN: 10556

Middle Eastern (MID) AF: 0.531 AC: 154 AN: 290

European-Non Finnish (NFE) AF: 0.538 AC: 36555 AN: 67960

Other (OTH) AF: 0.553 AC: 1167 AN: 2110

Alfa AF: 0.558 Hom.: 4219

Bravo AF: 0.581

Asia WGS AF: 0.554 AC: 1925 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.20
DANN	Benign	0.29
PhyloP100		-3.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4646047; hg19: chr1-15831783;