chr4-8597740-G-C

Position:

• chr4-8597740-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001014447.3(CPZ):​c.89-1713G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 152,232 control chromosomes in the GnomAD database, including 12,830 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.40 (12827 hom., cov: 34)
  • Exomes 𝑓: 0.44 (3 hom.)
• Consequence: CPZ NM_001014447.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.33

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPZ	NM_001014447.3	c.89-1713G>C		intron_variant		ENST00000360986.9	NP_001014447.2
CPZ	NM_003652.4	c.89-3383G>C		intron_variant			NP_003643.3
CPZ	NM_001014448.3	c.-586-1713G>C		intron_variant			NP_001014448.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPZ	ENST00000360986.9	c.89-1713G>C		intron_variant		1	NM_001014447.3	ENSP00000354255.4

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60490 AN: 152080 Hom.: 12826 Cov.: 34

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.497

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.613

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.456

GnomAD4 exome AF: 0.441 AC: 15 AN: 34 Hom.: 3 AF XY: 0.500 AC XY: 14 AN XY: 28

Gnomad4 FIN exome AF: 0.333

Gnomad4 NFE exome AF: 0.625

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.398 AC: 60514 AN: 152198 Hom.: 12827 Cov.: 34 AF XY: 0.402 AC XY: 29942 AN XY: 74404

Gnomad4 AFR AF: 0.262

Gnomad4 AMR AF: 0.440

Gnomad4 ASJ AF: 0.584

Gnomad4 EAS AF: 0.614

Gnomad4 SAS AF: 0.524

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.432

Gnomad4 OTH AF: 0.454

Alfa AF: 0.228 Hom.: 498

Bravo AF: 0.396

Asia WGS AF: 0.544 AC: 1893 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.21
DANN	Benign	0.47

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: rs3796734; hg19: chr4-8599467;