4-8592844-C-A

Position:

• chr4-8592844-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001014447.3(CPZ):​c.11C>A​(p.Pro4Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000753 in 1,328,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: CPZ NM_001014447.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0550

Genes affected

CPZ (HGNC:2333): (carboxypeptidase Z) This gene encodes a member of the metallocarboxypeptidase family. This enzyme displays carboxypeptidase activity towards substrates with basic C-terminal residues. It is most active at neutral pH and is inhibited by active site-directed inhibitors of metallocarboxypeptidases. Alternative splicing in the coding region results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

CPZ (HGNC:):

GPR78 (HGNC:4528): (G protein-coupled receptor 78) The protein encoded by this gene belongs to the G protein-coupled receptor family, which contain 7 transmembrane domains and transduce extracellular signals through heterotrimeric G proteins. This is an orphan receptor, which displays significant level of constitutive activity. Association analysis shows preliminary evidence for the involvement of this gene in susceptibility to bipolar affective disorder and schizophrenia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10220736).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPZ	NM_001014447.3	c.11C>A	p.Pro4Gln	missense_variant	1/11	ENST00000360986.9	NP_001014447.2
CPZ	NM_003652.4	c.11C>A	p.Pro4Gln	missense_variant	1/10		NP_003643.3
CPZ	NM_001014448.3	c.-664C>A		5_prime_UTR_variant	1/11		NP_001014448.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPZ	ENST00000360986.9	c.11C>A	p.Pro4Gln	missense_variant	1/11	1	NM_001014447.3	ENSP00000354255.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.53e-7 AC: 1 AN: 1328762 Hom.: 0 Cov.: 28 AF XY: 0.00000153 AC XY: 1 AN XY: 653816

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.49e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000618 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2021

The c.11C>A (p.P4Q) alteration is located in exon 1 (coding exon 1) of the CPZ gene. This alteration results from a C to A substitution at nucleotide position 11, causing the proline (P) at amino acid position 4 to be replaced by a glutamine (Q). 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	0.090
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.5
DANN	Benign	0.89
DEOGEN2	Benign	0.0098	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.36	N;N
REVEL	Benign	0.022
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.25	B;B
Vest4		0.25
MutPred		0.31		Loss of glycosylation at P3 (P = 0.0012);Loss of glycosylation at P3 (P = 0.0012);
MVP		0.22
MPC		0.0038
ClinPred		0.060	T
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.12
gMVP		0.67

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: rs370877808; hg19: chr4-8594571;