11-104951922-T-C

Position:

• chr11-104951922-T-C

Variant summary

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

The NM_001225.4(CASP4):​c.346A>G​(p.Arg116Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASP4 NM_001225.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06

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 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=0.23300636).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP4	NM_001225.4	c.346A>G	p.Arg116Gly	missense_variant	3/9	ENST00000444739.7	NP_001216.1
CASP4	NM_033306.3	c.178A>G	p.Arg60Gly	missense_variant	4/10		NP_150649.1
CASP4	XM_011543019.2	c.73A>G	p.Arg25Gly	missense_variant	2/8		XP_011541321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP4	ENST00000444739.7	c.346A>G	p.Arg116Gly	missense_variant	3/9	1	NM_001225.4	ENSP00000388566.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2024

The c.346A>G (p.R116G) alteration is located in exon 3 (coding exon 3) of the CASP4 gene. This alteration results from a A to G substitution at nucleotide position 346, causing the arginine (R) at amino acid position 116 to be replaced by a glycine (G). 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	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.36	T;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.026	D;D;.
Polyphen		0.0080	B;.;.
Vest4		0.17
MutPred		0.44		Loss of stability (P = 0.0468);.;Loss of stability (P = 0.0468);
MVP		0.54
MPC		0.091
ClinPred		0.89	D
GERP RS		4.0
Varity_R		0.41
gMVP		0.40

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-104822649;