7-130308381-G-A

Variant names:

• chr7-130308381-G-A
• rs145012020
• NM_016352.4:c.777G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_016352.4(CPA4):​c.777G>A​(p.Trp259*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00361 in 1,614,060 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (16 hom.)
• Consequence: CPA4 NM_016352.4 stop_gained
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 7.14

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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 7-130308381-G-A is Benign according to our data. Variant chr7-130308381-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 776598.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-130308381-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPA4	NM_016352.4	c.777G>A	p.Trp259*	stop_gained	Exon 8 of 11	ENST00000222482.10	NP_057436.2
CPA4	NM_001163446.2	c.678G>A	p.Trp226*	stop_gained	Exon 7 of 10		NP_001156918.1
CPA4	XM_047420438.1	c.465G>A	p.Trp155*	stop_gained	Exon 8 of 11		XP_047276394.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPA4	ENST00000222482.10	c.777G>A	p.Trp259*	stop_gained	Exon 8 of 11	1	NM_016352.4	ENSP00000222482.4
CPA4	ENST00000445470.6	c.678G>A	p.Trp226*	stop_gained	Exon 7 of 10	2		ENSP00000412947.2
CPA4	ENST00000493259.5	c.465G>A	p.Trp155*	stop_gained	Exon 6 of 9	2		ENSP00000419660.1
CPA4	ENST00000488025.1	n.250G>A		non_coding_transcript_exon_variant	Exon 1 of 3	4

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 377 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00385

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00234 AC: 588 AN: 251442 Hom.: 0 AF XY: 0.00254 AC XY: 345 AN XY: 135896

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00209

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00349

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00373 AC: 5453 AN: 1461758 Hom.: 16 Cov.: 30 AF XY: 0.00365 AC XY: 2652 AN XY: 727190

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00402

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00238

Gnomad4 FIN exome AF: 0.000861

Gnomad4 NFE exome AF: 0.00433

Gnomad4 OTH exome AF: 0.00315

GnomAD4 genome AF: 0.00248 AC: 377 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.00222 AC XY: 165 AN XY: 74470

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00385

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00376 Hom.: 2

Bravo AF: 0.00265

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00235 AC: 285

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00427

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 24, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CPA4-related disorder Benign:1

Jul 19, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	48
DANN	Uncertain	0.99
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.81	D
Vest4		0.27, 0.27, 0.24
GERP RS		5.8

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: rs145012020; hg19: chr7-129948221; COSMIC: COSV55984875; COSMIC: COSV55984875;