4-8592824-C-T

Position:

• chr4-8592824-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001014447.3(CPZ):​c.-10C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,457,286 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0019 (5 hom.)
• Consequence: CPZ NM_001014447.3 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.272

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 4-8592824-C-T is Benign according to our data. Variant chr4-8592824-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3037364.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPZ	NM_001014447.3	c.-10C>T		5_prime_UTR_variant	1/11	ENST00000360986.9	NP_001014447.2
CPZ	NM_003652.4	c.-10C>T		5_prime_UTR_variant	1/10		NP_003643.3
CPZ	NM_001014448.3	c.-684C>T		5_prime_UTR_variant	1/11		NP_001014448.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPZ	ENST00000360986	c.-10C>T		5_prime_UTR_variant	1/11	1	NM_001014447.3	ENSP00000354255.4

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 152174 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00185

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00106 AC: 64 AN: 60492 Hom.: 0 AF XY: 0.000795 AC XY: 27 AN XY: 33978

Gnomad AFR exome AF: 0.000661

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00247

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.000556

GnomAD4 exome AF: 0.00190 AC: 2479 AN: 1305000 Hom.: 5 Cov.: 28 AF XY: 0.00188 AC XY: 1205 AN XY: 639694

Gnomad4 AFR exome AF: 0.000340

Gnomad4 AMR exome AF: 0.000444

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00213

Gnomad4 NFE exome AF: 0.00216

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00121 AC: 185 AN: 152286 Hom.: 0 Cov.: 34 AF XY: 0.000980 AC XY: 73 AN XY: 74456

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.00185

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00162 Hom.: 2

Bravo AF: 0.00111

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CPZ-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	13
DANN	Benign	0.97

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: rs368876185; hg19: chr4-8594551;