Genetic Variant CASP9:p.Phe319Leu (chr1-15495366-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001229.5(CASP9):c.955T>C(p.Phe319Leu) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 29)

Consequence

CASP9
NM_001229.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.48

Publications

0 publications found

Variant links:

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]

CASP9 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1433416).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001229.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASP9	NM_001229.5	MANE Select	c.955T>C	p.Phe319Leu	missense	Exon 7 of 9	NP_001220.2
CASP9	NM_032996.3		c.706T>C	p.Phe236Leu	missense	Exon 7 of 9	NP_127463.2	P55211-4
CASP9	NM_001278054.2		c.505T>C	p.Phe169Leu	missense	Exon 3 of 5	NP_001264983.1	P55211-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASP9	ENST00000333868.10	TSL:1 MANE Select	c.955T>C	p.Phe319Leu	missense	Exon 7 of 9	ENSP00000330237.5	P55211-1
CASP9	ENST00000348549.9	TSL:1	c.505T>C	p.Phe169Leu	missense	Exon 3 of 5	ENSP00000255256.7	P55211-2
CASP9	ENST00000400777.7	TSL:1	n.*548T>C		non_coding_transcript_exon	Exon 7 of 9	ENSP00000383588.3	H0Y3S8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.10

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.67

M_CAP

Benign

0.012

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

2.5

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-2.2

REVEL

Benign

0.13

Sift

Benign

0.33

Sift4G

Benign

0.15

Polyphen

0.0040

Vest4

0.18

MutPred

0.30

Gain of relative solvent accessibility (P = 0.005)

MVP

0.48

MPC

0.15

ClinPred

0.55

GERP RS

5.1

Varity_R

0.36

gMVP

0.26

Mutation Taster

=61/39

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over