11-104954870-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001225.4(CASP4):c.139G>A(p.Asp47Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00486 in 1,613,718 control chromosomes in the GnomAD database, including 353 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 184 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 169 hom. )

Consequence

CASP4
NM_001225.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.497

Publications

7 publications found

Variant links:

Genes affected

CASP4 (HGNC:1505): (caspase 4) This gene encodes a protein that is 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 composed of a prodomain and a large and small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This caspase is able to cleave and activate its own precursor protein, as well as caspase 1 precursor. When overexpressed, this gene induces cell apoptosis. Alternative splicing results in transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

CASP4 links:

ENSG00000303891 (HGNC:):

ENSG00000303891 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038125515).

BP6

Variant 11-104954870-C-T is Benign according to our data. Variant chr11-104954870-C-T is described in ClinVar as Benign. ClinVar VariationId is 787097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001225.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP4	NM_001225.4	MANE Select	c.139G>A	p.Asp47Asn	missense	Exon 2 of 9	NP_001216.1	P49662-1
	CASP4	NM_033306.3		c.-30G>A		5_prime_UTR	Exon 3 of 10	NP_150649.1	P49662-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASP4	ENST00000444739.7	TSL:1 MANE Select	c.139G>A	p.Asp47Asn	missense	Exon 2 of 9	ENSP00000388566.2	P49662-1
CASP4	ENST00000393150.7	TSL:1	c.-30G>A		5_prime_UTR	Exon 2 of 9	ENSP00000376857.3	P49662-2
CASP4	ENST00000533730.5	TSL:1	n.161G>A		non_coding_transcript_exon	Exon 2 of 8

Frequencies

GnomAD3 genomes

AF:

0.0253

AC:

3853

AN:

152098

Hom.:

184

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.0210

GnomAD2 exomes

AF:

0.00636

AC:

1596

AN:

250958

AF XY:

0.00470

show subpopulations

Gnomad AFR exome

AF:

0.0850

Gnomad AMR exome

AF:

0.00441

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000353

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00273

AC:

3984

AN:

1461502

Hom.:

169

Cov.:

AF XY:

0.00236

AC XY:

1716

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.0927

AC:

3100

AN:

33450

American (AMR)

AF:

0.00544

AC:

243

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26122

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39684

South Asian (SAS)

AF:

0.000197

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00434

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000192

AC:

213

AN:

1111786

Other (OTH)

AF:

0.00629

AC:

380

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

213

425

638

850

1063

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

294

392

490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0254

AC:

3859

AN:

152216

Hom.:

184

Cov.:

AF XY:

0.0249

AC XY:

1856

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0867

AC:

3602

AN:

41532

American (AMR)

AF:

0.0115

AC:

176

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000415

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68014

Other (OTH)

AF:

0.0208

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

179

358

538

717

896

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00919

Hom.:

116

Bravo

AF:

0.0290

ESP6500AA

AF:

0.0820

AC:

361

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00769

AC:

934

Asia WGS

AF:

0.00318

AC:

AN:

3476

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.99

(source)

DANN

Benign

0.15

DEOGEN2

Benign

0.036

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0038

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.95

PhyloP100

-0.50

PrimateAI

Benign

0.30

PROVEAN

Benign

0.25

REVEL

Benign

0.0090

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.083

MVP

0.088

MPC

0.070

ClinPred

0.0021

GERP RS

0.023

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.027

gMVP

0.10

Mutation Taster

=300/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over