11-104947566-A-G

Position:

• chr11-104947566-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001225.4(CASP4):​c.926-374T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 154,278 control chromosomes in the GnomAD database, including 4,283 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.23 (4230 hom., cov: 32)
  • Exomes 𝑓: 0.20 (53 hom.)
• Consequence: CASP4 NM_001225.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.854

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP4	NM_001225.4	c.926-374T>C		intron_variant		ENST00000444739.7	NP_001216.1
CASP4	NM_033306.3	c.758-374T>C		intron_variant			NP_150649.1
CASP4	XM_011543019.2	c.653-374T>C		intron_variant			XP_011541321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP4	ENST00000444739.7	c.926-374T>C		intron_variant		1	NM_001225.4	ENSP00000388566.2

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34795 AN: 151974 Hom.: 4223 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.244

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.0905

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.233

GnomAD4 exome AF: 0.204 AC: 447 AN: 2186 Hom.: 53 Cov.: 0 AF XY: 0.214 AC XY: 255 AN XY: 1190

Gnomad4 AFR exome AF: 0.300

Gnomad4 AMR exome AF: 0.278

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.0625

Gnomad4 SAS exome AF: 0.205

Gnomad4 FIN exome AF: 0.235

Gnomad4 NFE exome AF: 0.203

Gnomad4 OTH exome AF: 0.169

GnomAD4 genome AF: 0.229 AC: 34837 AN: 152092 Hom.: 4230 Cov.: 32 AF XY: 0.232 AC XY: 17280 AN XY: 74342

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.279

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.0903

Gnomad4 SAS AF: 0.209

Gnomad4 FIN AF: 0.292

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.233

Alfa AF: 0.211 Hom.: 5297

Bravo AF: 0.233

Asia WGS AF: 0.175 AC: 606 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.7
DANN	Benign	0.80

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: rs11226565; hg19: chr11-104818293;