chr11-104954870-C-T

Position:

• chr11-104954870-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.025 (184 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (169 hom.)
• Consequence: CASP4 NM_001225.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.497

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP4	NM_001225.4	c.139G>A	p.Asp47Asn	missense_variant	2/9	ENST00000444739.7	NP_001216.1
CASP4	NM_033306.3	c.-30G>A		5_prime_UTR_variant	3/10		NP_150649.1
CASP4	XM_011543019.2	c.-193G>A		upstream_gene_variant			XP_011541321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP4	ENST00000444739.7	c.139G>A	p.Asp47Asn	missense_variant	2/9	1	NM_001225.4	ENSP00000388566.2

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3853 AN: 152098 Hom.: 184 Cov.: 32

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

GnomAD3 exomes AF: 0.00636 AC: 1596 AN: 250958 Hom.: 64 AF XY: 0.00470 AC XY: 637 AN XY: 135634

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 SAS exome AF: 0.000163

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.: 32 AF XY: 0.00236 AC XY: 1716 AN XY: 727052

Gnomad4 AFR exome AF: 0.0927

Gnomad4 AMR exome AF: 0.00544

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000192

Gnomad4 OTH exome AF: 0.00629

GnomAD4 genome AF: 0.0254 AC: 3859 AN: 152216 Hom.: 184 Cov.: 32 AF XY: 0.0249 AC XY: 1856 AN XY: 74422

Gnomad4 AFR AF: 0.0867

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.00438 Hom.: 45

Bravo AF: 0.0290

ESP6500AA AF: 0.0820 AC: 361

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00769 AC: 934

Asia WGS AF: 0.00318 AC: 11 AN: 3476

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.99
DANN	Benign	0.15
DEOGEN2	Benign	0.036	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.55	T;T
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.95	L;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.25	N;N
REVEL	Benign	0.0090
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;.
Polyphen		0.0020	B;.
Vest4		0.083
MVP		0.088
MPC		0.070
ClinPred		0.0021	T
GERP RS		0.023
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.10

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: rs56226603; hg19: chr11-104825597; COSMIC: COSV101274245; COSMIC: COSV101274245;