NM_001014447.3:c.1227+2024A>C

Variant names:

• chr4-8609449-A-C
• rs4696715
• NM_001014447.3:c.1227+2024A>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.1227+2024A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 141,712 control chromosomes in the GnomAD database, including 6,272 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 0.30 (6272 hom., cov: 35)
• Consequence: CPZ NM_001014447.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.376
• Publications: 3 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]

LOC124900659 (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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPZ	NM_001014447.3	c.1227+2024A>C		intron_variant	Intron 7 of 10	ENST00000360986.9	NP_001014447.2
LOC124900659	XR_007058014.1	n.3729T>G		non_coding_transcript_exon_variant	Exon 3 of 3
CPZ	NM_003652.4	c.1194+2024A>C		intron_variant	Intron 6 of 9		NP_003643.3
CPZ	NM_001014448.3	c.816+2024A>C		intron_variant	Intron 7 of 10		NP_001014448.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPZ	ENST00000360986.9	c.1227+2024A>C		intron_variant	Intron 7 of 10	1	NM_001014447.3	ENSP00000354255.4

Frequencies

GnomAD3 genomes AF: 0.300 AC: 42548 AN: 141620 Hom.: 6269 Cov.: 35

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.307

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.300 AC: 42565 AN: 141712 Hom.: 6272 Cov.: 35 AF XY: 0.297 AC XY: 20640 AN XY: 69560

African (AFR) AF: 0.300 AC: 9567 AN: 31856

American (AMR) AF: 0.250 AC: 3735 AN: 14922

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 918 AN: 3448

East Asian (EAS) AF: 0.343 AC: 1774 AN: 5174

South Asian (SAS) AF: 0.147 AC: 709 AN: 4818

European-Finnish (FIN) AF: 0.334 AC: 3526 AN: 10548

Middle Eastern (MID) AF: 0.246 AC: 70 AN: 284

European-Non Finnish (NFE) AF: 0.316 AC: 21410 AN: 67742

Other (OTH) AF: 0.308 AC: 620 AN: 2010

Alfa AF: 0.276 Hom.: 3323

Bravo AF: 0.273

Asia WGS AF: 0.247 AC: 858 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.7
DANN	Benign	0.49
PhyloP100		0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs4696715; hg19: chr4-8611176;