Genetic Variant CASP7:p.Phe181Leu (chr10-113725526-T-C) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP3BP4_StrongBP6_ModerateBS2

The NM_001227.5(CASP7):c.541T>C(p.Phe181Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00335 in 1,551,130 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0035 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 19 hom. )

Consequence

CASP7
NM_001227.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.03

Variant links:

Genes affected

CASP7 (HGNC:1508): (caspase 7) 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. The precursor of the encoded protein is cleaved by caspase 3 and 10, is activated upon cell death stimuli and induces apoptosis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

CASP7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, FATHMM_MKL, MutationAssessor, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.0149098635).

BP6

Variant 10-113725526-T-C is Benign according to our data. Variant chr10-113725526-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2640854.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 531 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP7	NM_001227.5 link	c.541T>C	p.Phe181Leu	missense_variant	Exon 5 of 7	ENST00000369318.8	NP_001218.1	P55210-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP7	ENST00000369318.8 link	c.541T>C	p.Phe181Leu	missense_variant	Exon 5 of 7	1	NM_001227.5	ENSP00000358324.4		P55210-1

Frequencies

GnomAD3 genomes

AF:

0.00350

AC:

532

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0223

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00360

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00427

AC:

859

AN:

201296

AF XY:

0.00436

show subpopulations

Gnomad AFR exome

AF:

0.000545

Gnomad AMR exome

AF:

0.000535

Gnomad ASJ exome

AF:

0.00384

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0203

Gnomad NFE exome

AF:

0.00351

Gnomad OTH exome

AF:

0.00397

GnomAD4 exome

AF:

0.00333

AC:

4664

AN:

1398822

Hom.:

Cov.:

AF XY:

0.00333

AC XY:

2304

AN XY:

691250

show subpopulations

African (AFR)

AF:

0.000297

AC:

AN:

30308

American (AMR)

AF:

0.000597

AC:

AN:

31832

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

23024

East Asian (EAS)

AF:

0.00

AC:

AN:

38170

South Asian (SAS)

AF:

0.00237

AC:

182

AN:

76924

European-Finnish (FIN)

AF:

0.0170

AC:

882

AN:

51776

Middle Eastern (MID)

AF:

0.000183

AC:

AN:

5456

European-Non Finnish (NFE)

AF:

0.00309

AC:

3350

AN:

1083906

Other (OTH)

AF:

0.00293

AC:

168

AN:

57426

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

203

406

610

813

1016

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00349

AC:

531

AN:

152308

Hom.:

Cov.:

AF XY:

0.00420

AC XY:

313

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000601

AC:

AN:

41564

American (AMR)

AF:

0.000457

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00186

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0223

AC:

237

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00359

AC:

244

AN:

68028

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

113

141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00283

Hom.:

Bravo

AF:

0.00169

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00348

AC:

423

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CASP7: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T;T;T;T;T;.;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;.;D;.;.;D;D

MetaRNN

Benign

0.015

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Pathogenic

3.1

M;.;M;.;M;M;.;.

PhyloP100

6.0

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.3

.;D;D;.;D;D;.;D

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

.;D;D;.;D;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D

Polyphen

1.0

D;.;D;.;D;D;D;.

Vest4

0.85

MutPred

0.73

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;

MVP

0.85

MPC

0.72

ClinPred

0.049

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.84

Mutation Taster

=41/59

disease causing

(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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10-113725526-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over