4-184631871-A-G

Variant names:

• chr4-184631871-A-G
• NM_004346.4:c.377T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004346.4(CASP3):​c.377T>C​(p.Ile126Thr) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CASP3 NM_004346.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01
• Publications: 0 publications found

Genes affected

CASP3 (HGNC:1504): (caspase 3) The protein encoded by this gene is a cysteine-aspartic acid protease that plays a central role in the execution-phase of cell apoptosis. The encoded protein cleaves and inactivates poly(ADP-ribose) polymerase while it cleaves and activates sterol regulatory element binding proteins as well as caspases 6, 7, and 9. This protein itself is processed by caspases 8, 9, and 10. It is the predominant caspase involved in the cleavage of amyloid-beta 4A precursor protein, which is associated with neuronal death in Alzheimer's disease. [provided by RefSeq, Aug 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26676798).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP3	NM_004346.4	c.377T>C	p.Ile126Thr	missense_variant	Exon 6 of 8	ENST00000308394.9	NP_004337.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP3	ENST00000308394.9	c.377T>C	p.Ile126Thr	missense_variant	Exon 6 of 8	1	NM_004346.4	ENSP00000311032.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.377T>C (p.I126T) alteration is located in exon 6 (coding exon 4) of the CASP3 gene. This alteration results from a T to C substitution at nucleotide position 377, causing the isoleucine (I) at amino acid position 126 to be replaced by a threonine (T). 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	0.23
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	.;T;T;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.78	.;.;T;.;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.42	.;N;N;.;.
PhyloP100		2.0
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.4	N;D;D;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Benign	0.074	T;T;T;T;T
Polyphen		0.89	P;B;B;P;P
Vest4		0.15
MutPred		0.69		Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);
MVP		0.67
MPC		0.80
ClinPred		0.17	T
GERP RS		-3.3
Varity_R		0.23
gMVP		0.56
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

hg19: chr4-185553025;