4-8601184-C-A

Position:

• chr4-8601184-C-A

Variant summary

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

The NM_001014447.3(CPZ):​c.183C>A​(p.Phe61Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 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)
• Consequence: CPZ NM_001014447.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPZ	NM_001014447.3	c.183C>A	p.Phe61Leu	missense_variant	3/11	ENST00000360986.9	NP_001014447.2
CPZ	NM_003652.4	c.150C>A	p.Phe50Leu	missense_variant	2/10		NP_003643.3
CPZ	NM_001014448.3	c.-229C>A		5_prime_UTR_variant	3/11		NP_001014448.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPZ	ENST00000360986.9	c.183C>A	p.Phe61Leu	missense_variant	3/11	1	NM_001014447.3	ENSP00000354255.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 34

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

Feb 22, 2023

The c.183C>A (p.F61L) alteration is located in exon 3 (coding exon 3) of the CPZ gene. This alteration results from a C to A substitution at nucleotide position 183, causing the phenylalanine (F) at amino acid position 61 to be replaced by a leucine (L). 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	Pathogenic	0.91
BayesDel_addAF	Benign	0.0031	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.046	T;.
Eigen	Benign	0.078
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.14	T;T
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.64	P;P
Vest4		0.38
MutPred		0.62		Gain of glycosylation at Y56 (P = 0.0323);.;
MVP		0.80
MPC		0.0064
ClinPred		0.79	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-8602911;