rs34069356

Variant names:

• chr20-58995705-C-T
• rs34069356
• NM_001336.4:c.856G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001336.4(CTSZ):​c.856G>A​(p.Ala286Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000822 in 1,614,180 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.0041 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (3 hom.)
• Consequence: CTSZ NM_001336.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23

Genes affected

CTSZ (HGNC:2547): (cathepsin Z) The protein encoded by this gene is a lysosomal cysteine proteinase and member of the peptidase C1 family. It exhibits both carboxy-monopeptidase and carboxy-dipeptidase activities. The encoded protein has also been known as cathepsin X and cathepsin P. This gene is expressed ubiquitously in cancer cell lines and primary tumors and, like other members of this family, may be involved in tumorigenesis. [provided by RefSeq, Oct 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034630299).
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000481 (703/1461874) while in subpopulation AFR AF = 0.0175 (587/33478). AF 95% confidence interval is 0.0164. There are 3 homozygotes in GnomAdExome4. There are 294 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSZ	NM_001336.4	c.856G>A	p.Ala286Thr	missense_variant	Exon 6 of 6	ENST00000217131.6	NP_001327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSZ	ENST00000217131.6	c.856G>A	p.Ala286Thr	missense_variant	Exon 6 of 6	1	NM_001336.4	ENSP00000217131.5

Frequencies

GnomAD3 genomes AF: 0.00408 AC: 621 AN: 152188 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00108 AC: 271 AN: 251252 AF XY: 0.000773

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000481 AC: 703 AN: 1461874 Hom.: 3 Cov.: 31 AF XY: 0.000404 AC XY: 294 AN XY: 727238

Gnomad4 AFR exome AF: 0.0175 AC: 587 AN: 33478

Gnomad4 AMR exome AF: 0.000268 AC: 12 AN: 44722

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.0000348 AC: 3 AN: 86256

Gnomad4 FIN exome AF: 0.000131 AC: 7 AN: 53420

Gnomad4 NFE exome AF: 0.0000261 AC: 29 AN: 1111998

Gnomad4 Remaining exome AF: 0.00103 AC: 62 AN: 60396

GnomAD4 genome AF: 0.00410 AC: 624 AN: 152306 Hom.: 11 Cov.: 32 AF XY: 0.00368 AC XY: 274 AN XY: 74482

Gnomad4 AFR AF: 0.0142 AC: 0.0142177 AN: 0.0142177

Gnomad4 AMR AF: 0.00144 AC: 0.00143828 AN: 0.00143828

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000441 AC: 0.0000440995 AN: 0.0000440995

Gnomad4 OTH AF: 0.00378 AC: 0.00378072 AN: 0.00378072

Alfa AF: 0.00192 Hom.: 2

Bravo AF: 0.00512

ESP6500AA AF: 0.0145 AC: 64

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00137 AC: 167

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.099	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.030
Sift	Benign	0.55	T
Sift4G	Benign	0.47	T
Polyphen		0.0010	B
Vest4		0.046
MVP		0.31
MPC		0.27
ClinPred		0.0030	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040
gMVP		0.65
Mutation Taster		=93/7	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

Publications

LitVar

Other links and lift over

dbSNP: rs34069356; hg19: chr20-57570760; COSMIC: COSV53882598; COSMIC: COSV53882598;