4-8597740-G-C

Variant names:

• chr4-8597740-G-C
• rs3796734
• NM_001014447.3:c.89-1713G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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]

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001014447.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPZ	NM_001014447.3	MANE Select	c.89-1713G>C		intron	N/A	NP_001014447.2	Q66K79-1
	CPZ	NM_003652.4		c.89-3383G>C		intron	N/A	NP_003643.3	Q66K79-2
	CPZ	NM_001014448.3		c.-586-1713G>C		intron	N/A	NP_001014448.2	Q66K79-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPZ	ENST00000360986.9	TSL:1 MANE Select	c.89-1713G>C		intron	N/A	ENSP00000354255.4	Q66K79-1
	CPZ	ENST00000315782.6	TSL:1	c.89-3383G>C		intron	N/A	ENSP00000315074.6	Q66K79-2
	CPZ	ENST00000382480.6	TSL:1	c.-586-1713G>C		intron	N/A	ENSP00000371920.2	Q66K79-3

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.333 AC: 4 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.625 AC: 10 AN: 16

Other (OTH) AF: 0.167 AC: 1 AN: 6

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

African (AFR) AF: 0.262 AC: 10902 AN: 41536

American (AMR) AF: 0.440 AC: 6726 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 2027 AN: 3470

East Asian (EAS) AF: 0.614 AC: 3165 AN: 5158

South Asian (SAS) AF: 0.524 AC: 2529 AN: 4822

European-Finnish (FIN) AF: 0.399 AC: 4228 AN: 10602

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.432 AC: 29383 AN: 67990

Other (OTH) AF: 0.454 AC: 959 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.21
DANN	Benign	0.47
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3796734; hg19: chr4-8599467;