1-15524118-G-A

Variant names:

• chr1-15524118-G-A
• rs1052571
• NM_001229.5:c.83C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001229.5(CASP9):​c.83C>T​(p.Ala28Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 1,537,426 control chromosomes in the GnomAD database, including 223,949 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A28T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.59 (26741 hom., cov: 32)
  • Exomes 𝑓: 0.53 (197208 hom.)
• Consequence: CASP9 NM_001229.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.25
• Publications: 64 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.70045E-6).
• BP6: Variant 1-15524118-G-A is Benign according to our data. Variant chr1-15524118-G-A is described in ClinVar as Benign. ClinVar VariationId is 1275295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP9	NM_001229.5	MANE Select	c.83C>T	p.Ala28Val	missense	Exon 1 of 9	NP_001220.2
	CASP9	NM_001278054.2		c.83C>T	p.Ala28Val	missense	Exon 1 of 5	NP_001264983.1
	CASP9	NR_102732.2		n.98C>T		non_coding_transcript_exon	Exon 1 of 9

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP9	ENST00000333868.10	TSL:1 MANE Select	c.83C>T	p.Ala28Val	missense	Exon 1 of 9	ENSP00000330237.5
	CASP9	ENST00000348549.9	TSL:1	c.83C>T	p.Ala28Val	missense	Exon 1 of 5	ENSP00000255256.7
	CASP9	ENST00000400777.7	TSL:1	n.74C>T		non_coding_transcript_exon	Exon 1 of 9	ENSP00000383588.3

Frequencies

GnomAD3 genomes AF: 0.586 AC: 88922 AN: 151748 Hom.: 26703 Cov.: 32

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.651

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.555

GnomAD2 exomes AF: 0.503 AC: 68365 AN: 135782 AF XY: 0.499

Gnomad AFR exome AF: 0.685

Gnomad AMR exome AF: 0.415

Gnomad ASJ exome AF: 0.490

Gnomad EAS exome AF: 0.631

Gnomad FIN exome AF: 0.617

Gnomad NFE exome AF: 0.513

Gnomad OTH exome AF: 0.500

GnomAD4 exome AF: 0.530 AC: 734459 AN: 1385566 Hom.: 197208 Cov.: 52 AF XY: 0.527 AC XY: 360833 AN XY: 684316

African (AFR) AF: 0.703 AC: 21625 AN: 30778

American (AMR) AF: 0.426 AC: 15115 AN: 35458

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 12302 AN: 24900

East Asian (EAS) AF: 0.640 AC: 22614 AN: 35340

South Asian (SAS) AF: 0.431 AC: 33982 AN: 78866

European-Finnish (FIN) AF: 0.626 AC: 25006 AN: 39952

Middle Eastern (MID) AF: 0.481 AC: 1954 AN: 4064

European-Non Finnish (NFE) AF: 0.529 AC: 570984 AN: 1078612

Other (OTH) AF: 0.536 AC: 30877 AN: 57596

GnomAD4 genome AF: 0.586 AC: 89003 AN: 151860 Hom.: 26741 Cov.: 32 AF XY: 0.587 AC XY: 43516 AN XY: 74194

African (AFR) AF: 0.705 AC: 29166 AN: 41382

American (AMR) AF: 0.498 AC: 7618 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1709 AN: 3468

East Asian (EAS) AF: 0.646 AC: 3330 AN: 5154

South Asian (SAS) AF: 0.424 AC: 2043 AN: 4816

European-Finnish (FIN) AF: 0.651 AC: 6855 AN: 10538

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.538 AC: 36499 AN: 67904

Other (OTH) AF: 0.551 AC: 1160 AN: 2106

Alfa AF: 0.545 Hom.: 56899

Bravo AF: 0.580

ExAC AF: 0.357 AC: 33850

Asia WGS AF: 0.542 AC: 1874 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 23, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27984487)

CASP9-related disorder Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0000057	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.0050
Sift	Benign	0.53	T
Sift4G	Benign	0.13	T
Polyphen		0.029	B
Vest4		0.039
MPC		0.12
ClinPred		0.021	T
GERP RS		1.3
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.35
gMVP		0.11
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1052571; hg19: chr1-15850613; COSMIC: COSV61600760; COSMIC: COSV61600760;