11-105007200-T-C

Variant names:

• chr11-105007200-T-C
• rs507879
• NM_004347.5:c.316A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004347.5(CASP5):​c.316A>G​(p.Thr106Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 1,612,524 control chromosomes in the GnomAD database, including 162,981 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.49 (18606 hom., cov: 32)
  • Exomes 𝑓: 0.44 (144375 hom.)
• Consequence: CASP5 NM_004347.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.150
• Publications: 56 publications found

Genes affected

CASP5 (HGNC:1506): (caspase 5) This gene encodes 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 which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. Overexpression of the active form of this enzyme induces apoptosis in fibroblasts. Max, a central component of the Myc/Max/Mad transcription regulation network important for cell growth, differentiation, and apoptosis, is cleaved by this protein; this process requires Fas-mediated dephosphorylation of Max. The expression of this gene is regulated by interferon-gamma and lipopolysaccharide. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

ENSG00000303891 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0572106E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004347.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP5	NM_004347.5	MANE Select	c.316A>G	p.Thr106Ala	missense	Exon 3 of 10	NP_004338.3
	CASP5	NM_001136112.3		c.355A>G	p.Thr119Ala	missense	Exon 3 of 10	NP_001129584.1
	CASP5	NM_001136109.3		c.142A>G	p.Thr48Ala	missense	Exon 2 of 9	NP_001129581.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP5	ENST00000260315.8	TSL:5 MANE Select	c.316A>G	p.Thr106Ala	missense	Exon 3 of 10	ENSP00000260315.3
	CASP5	ENST00000393141.6	TSL:5	c.355A>G	p.Thr119Ala	missense	Exon 3 of 10	ENSP00000376849.2
	CASP5	ENST00000526056.5	TSL:5	c.355A>G	p.Thr119Ala	missense	Exon 3 of 9	ENSP00000436877.1

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73689 AN: 151856 Hom.: 18579 Cov.: 32

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.403

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.449

Gnomad OTH AF: 0.456

GnomAD2 exomes AF: 0.434 AC: 108969 AN: 251040 AF XY: 0.427

Gnomad AFR exome AF: 0.616

Gnomad AMR exome AF: 0.505

Gnomad ASJ exome AF: 0.375

Gnomad EAS exome AF: 0.217

Gnomad FIN exome AF: 0.449

Gnomad NFE exome AF: 0.445

Gnomad OTH exome AF: 0.421

GnomAD4 exome AF: 0.441 AC: 643673 AN: 1460550 Hom.: 144375 Cov.: 40 AF XY: 0.437 AC XY: 317390 AN XY: 726630

African (AFR) AF: 0.615 AC: 20562 AN: 33452

American (AMR) AF: 0.502 AC: 22443 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 9625 AN: 26126

East Asian (EAS) AF: 0.239 AC: 9501 AN: 39672

South Asian (SAS) AF: 0.358 AC: 30859 AN: 86224

European-Finnish (FIN) AF: 0.447 AC: 23868 AN: 53346

Middle Eastern (MID) AF: 0.301 AC: 1734 AN: 5768

European-Non Finnish (NFE) AF: 0.449 AC: 499254 AN: 1110928

Other (OTH) AF: 0.428 AC: 25827 AN: 60342

GnomAD4 genome AF: 0.486 AC: 73784 AN: 151974 Hom.: 18606 Cov.: 32 AF XY: 0.484 AC XY: 35925 AN XY: 74254

African (AFR) AF: 0.618 AC: 25620 AN: 41466

American (AMR) AF: 0.485 AC: 7403 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1286 AN: 3464

East Asian (EAS) AF: 0.219 AC: 1132 AN: 5176

South Asian (SAS) AF: 0.359 AC: 1725 AN: 4810

European-Finnish (FIN) AF: 0.444 AC: 4684 AN: 10554

Middle Eastern (MID) AF: 0.336 AC: 98 AN: 292

European-Non Finnish (NFE) AF: 0.449 AC: 30502 AN: 67938

Other (OTH) AF: 0.458 AC: 967 AN: 2112

Alfa AF: 0.451 Hom.: 57624

Bravo AF: 0.492

TwinsUK AF: 0.457 AC: 1695

ALSPAC AF: 0.446 AC: 1719

ESP6500AA AF: 0.614 AC: 2704

ESP6500EA AF: 0.441 AC: 3788

ExAC AF: 0.435 AC: 52777

Asia WGS AF: 0.351 AC: 1218 AN: 3478

EpiCase AF: 0.428

EpiControl AF: 0.423

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.90
DANN	Benign	0.12
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00028	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.000011	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.9	N
PhyloP100		0.15
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.025
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.017
MPC		0.19
ClinPred		0.0036	T
GERP RS		2.5
Varity_R		0.025
gMVP		0.049
Mutation Taster		=99/1	polymorphism (auto)

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

dbSNP: rs507879; hg19: chr11-104877927; COSMIC: COSV52827778;