11-104949777-C-T

Variant names:

• chr11-104949777-C-T
• NM_001225.4:c.547G>A

Variant summary

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

The NM_001225.4(CASP4):​c.547G>A​(p.Asp183Asn) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. 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, splice_region
• Scores: Splicing: ADA: 0.9972
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.13

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP4	NM_001225.4	c.547G>A	p.Asp183Asn	missense_variant, splice_region_variant	Exon 5 of 9	ENST00000444739.7	NP_001216.1
CASP4	NM_033306.3	c.379G>A	p.Asp127Asn	missense_variant, splice_region_variant	Exon 6 of 10		NP_150649.1
CASP4	XM_011543019.2	c.274G>A	p.Asp92Asn	missense_variant, splice_region_variant	Exon 4 of 8		XP_011541321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP4	ENST00000444739.7	c.547G>A	p.Asp183Asn	missense_variant, splice_region_variant	Exon 5 of 9	1	NM_001225.4	ENSP00000388566.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.6	D;N
REVEL	Benign	0.12
Sift	Uncertain	0.021	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		0.045	B;.
Vest4		0.12
MutPred		0.58		Loss of phosphorylation at T180 (P = 0.1101);.;
MVP		0.31
MPC		0.070
ClinPred		0.91	D
GERP RS		4.6
Varity_R		0.19
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
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: chr11-104820504;