7-130299402-C-A

Variant summary

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

The NM_016352.4(CPA4):c.283C>A(p.Gln95Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPA4 NM_016352.4 missense, splice_region
• Scores: Splicing: ADA: 0.9252
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.23

Genes affected

CPA4 (HGNC:15740): (carboxypeptidase A4) This gene is a member of the carboxypeptidase A/B subfamily, and it is located in a cluster with three other family members on chromosome 7. Carboxypeptidases are zinc-containing exopeptidases that catalyze the release of carboxy-terminal amino acids, and are synthesized as zymogens that are activated by proteolytic cleavage. This gene could be involved in the histone hyperacetylation pathway. It is imprinted and may be a strong candidate gene for prostate cancer aggressiveness. [provided by RefSeq, Jul 2008]

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	UniProt
CPA4	NM_016352.4	c.283C>A	p.Gln95Lys	missense_variant, splice_region_variant	3/11	ENST00000222482.10
CPA4	NM_001163446.2	c.283C>A	p.Gln95Lys	missense_variant, splice_region_variant	3/10
CPA4	XM_047420438.1	c.-30C>A		splice_region_variant, 5_prime_UTR_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPA4	ENST00000222482.10	c.283C>A	p.Gln95Lys	missense_variant, splice_region_variant	3/11	1	NM_016352.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jan 23, 2024

The c.283C>A (p.Q95K) alteration is located in exon 3 (coding exon 3) of the CPA4 gene. This alteration results from a C to A substitution at nucleotide position 283, causing the glutamine (Q) at amino acid position 95 to be replaced by a lysine (K). 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	Benign	0.33
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.;.;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.0	M;M;.;.;M
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.44	T
Polyphen		1.0	D;.;.;.;D
Vest4		0.78, 0.72
MutPred		0.65		Gain of ubiquitination at Q95 (P = 0.0177);Gain of ubiquitination at Q95 (P = 0.0177);Gain of ubiquitination at Q95 (P = 0.0177);Gain of ubiquitination at Q95 (P = 0.0177);Gain of ubiquitination at Q95 (P = 0.0177);
MVP		0.66
MPC		0.63
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.88
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Pathogenic	0.79
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: chr7-129939242;