chr11-104948606-C-A

Position:

• chr11-104948606-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001225.4(CASP4):​c.852G>T​(p.Glu284Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,611,450 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.017 (80 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (54 hom.)
• Consequence: CASP4 NM_001225.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.04

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003347814).
• BP6: Variant 11-104948606-C-A is Benign according to our data. Variant chr11-104948606-C-A is described in ClinVar as [Benign]. Clinvar id is 787387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0582 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP4	NM_001225.4	c.852G>T	p.Glu284Asp	missense_variant	6/9	ENST00000444739.7	NP_001216.1
CASP4	NM_033306.3	c.684G>T	p.Glu228Asp	missense_variant	7/10		NP_150649.1
CASP4	XM_011543019.2	c.579G>T	p.Glu193Asp	missense_variant	5/8		XP_011541321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP4	ENST00000444739.7	c.852G>T	p.Glu284Asp	missense_variant	6/9	1	NM_001225.4	ENSP00000388566.2

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2599 AN: 152156 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.0602

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00452 AC: 1131 AN: 250406 Hom.: 29 AF XY: 0.00307 AC XY: 416 AN XY: 135336

Gnomad AFR exome AF: 0.0649

Gnomad AMR exome AF: 0.00167

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000987

GnomAD4 exome AF: 0.00169 AC: 2464 AN: 1459176 Hom.: 54 Cov.: 33 AF XY: 0.00141 AC XY: 1020 AN XY: 725806

Gnomad4 AFR exome AF: 0.0620

Gnomad4 AMR exome AF: 0.00211

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000817

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.00365

GnomAD4 genome AF: 0.0171 AC: 2604 AN: 152274 Hom.: 80 Cov.: 32 AF XY: 0.0161 AC XY: 1196 AN XY: 74454

Gnomad4 AFR AF: 0.0601

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00275 Hom.: 4

Bravo AF: 0.0191

ESP6500AA AF: 0.0652 AC: 287

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00584 AC: 709

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.084
DANN	Benign	0.89
DEOGEN2	Benign	0.088	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.55	T;T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.020
Sift	Benign	0.16	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.0	B;.
Vest4		0.058
MVP		0.12
MPC		0.065
ClinPred		0.0099	T
GERP RS		-2.6
Varity_R		0.091
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs55901059; hg19: chr11-104819333;