11-104944851-C-T

Position:

• chr11-104944851-C-T

Variant summary

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

The NM_001225.4(CASP4):​c.1036G>A​(p.Val346Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASP4 NM_001225.4 missense, splice_region
• Scores: Splicing: ADA: 0.3496
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.32

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP4	NM_001225.4	c.1036G>A	p.Val346Ile	missense_variant, splice_region_variant	8/9	ENST00000444739.7	NP_001216.1
CASP4	NM_033306.3	c.868G>A	p.Val290Ile	missense_variant, splice_region_variant	9/10		NP_150649.1
CASP4	XM_011543019.2	c.763G>A	p.Val255Ile	missense_variant, splice_region_variant	7/8		XP_011541321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP4	ENST00000444739.7	c.1036G>A	p.Val346Ile	missense_variant, splice_region_variant	8/9	1	NM_001225.4	ENSP00000388566.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

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

Apr 06, 2024

The c.1036G>A (p.V346I) alteration is located in exon 8 (coding exon 8) of the CASP4 gene. This alteration results from a G to A substitution at nucleotide position 1036, causing the valine (V) at amino acid position 346 to be replaced by an isoleucine (I). 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	0.21
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	0.082	D
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.92	N;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.023	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.98	D;.
Vest4		0.35
MutPred		0.71		Loss of disorder (P = 0.1587);.;
MVP		0.53
MPC		0.36
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.33
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.35
dbscSNV1_RF	Benign	0.32
SpliceAI score (max)		0.050		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: chr11-104815578; COSMIC: COSV67744310; COSMIC: COSV67744310;