11-104954881-T-C

Variant names:

• chr11-104954881-T-C
• rs1860700295
• NM_001225.4:c.128A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001225.4(CASP4):​c.128A>G​(p.Lys43Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CASP4 NM_001225.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.527

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12256312).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP4	NM_001225.4	c.128A>G	p.Lys43Arg	missense_variant	Exon 2 of 9	ENST00000444739.7	NP_001216.1
CASP4	NM_033306.3	c.-41A>G		5_prime_UTR_variant	Exon 3 of 10		NP_150649.1
CASP4	XM_011543019.2	c.-204A>G		upstream_gene_variant			XP_011541321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP4	ENST00000444739.7	c.128A>G	p.Lys43Arg	missense_variant	Exon 2 of 9	1	NM_001225.4	ENSP00000388566.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461486 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727050

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.128A>G (p.K43R) alteration is located in exon 2 (coding exon 2) of the CASP4 gene. This alteration results from a A to G substitution at nucleotide position 128, causing the lysine (K) at amino acid position 43 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.37	T;T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.051
Sift	Benign	0.10	T;T
Sift4G	Benign	0.45	T;.
Polyphen		0.47	P;.
Vest4		0.092
MutPred		0.40		Loss of ubiquitination at K43 (P = 0.0224);Loss of ubiquitination at K43 (P = 0.0224);
MVP		0.46
MPC		0.064
ClinPred		0.22	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.083
gMVP		0.19

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: rs1860700295; hg19: chr11-104825608;