1-15493903-G-A

Position:

• chr1-15493903-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001229.5(CASP9):​c.1147C>T​(p.Leu383Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CASP9 NM_001229.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38968784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP9	NM_001229.5	c.1147C>T	p.Leu383Phe	missense_variant	8/9	ENST00000333868.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP9	ENST00000333868.10	c.1147C>T	p.Leu383Phe	missense_variant	8/9	1	NM_001229.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1444284 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 716816

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2024

The c.1147C>T (p.L383F) alteration is located in exon 8 (coding exon 8) of the CASP9 gene. This alteration results from a C to T substitution at nucleotide position 1147, causing the leucine (L) at amino acid position 383 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;T;.;.
Eigen	Benign	0.017
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Pathogenic	3.3	.;M;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.4	N;N;N;D
REVEL	Benign	0.17
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		0.91	P;P;D;.
Vest4		0.27
MutPred		0.61		Loss of disorder (P = 0.176);Loss of disorder (P = 0.176);.;.;
MVP		0.81
MPC		0.53
ClinPred		0.95	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.66
gMVP		0.61

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: rs968455607; hg19: chr1-15820398;