11-104944851-C-T

Variant names:

• chr11-104944851-C-T
• NM_001225.4:c.1036G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

ENSG00000303891 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001225.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP4	NM_001225.4	MANE Select	c.1036G>A	p.Val346Ile	missense splice_region	Exon 8 of 9	NP_001216.1	P49662-1
	CASP4	NM_033306.3		c.868G>A	p.Val290Ile	missense splice_region	Exon 9 of 10	NP_150649.1	P49662-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP4	ENST00000444739.7	TSL:1 MANE Select	c.1036G>A	p.Val346Ile	missense splice_region	Exon 8 of 9	ENSP00000388566.2	P49662-1
	CASP4	ENST00000393150.7	TSL:1	c.868G>A	p.Val290Ile	missense splice_region	Exon 8 of 9	ENSP00000376857.3	P49662-2
	CASP4	ENST00000533730.5	TSL:1	n.1116G>A		splice_region non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.082	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.92	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.023	D
Sift4G	Pathogenic	0.0	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
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

hg19: chr11-104815578; COSMIC: COSV67744310; COSMIC: COSV67744310;