rs145012020

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 17 publications found

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

Our verdict: Likely_benign. The variant received -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 VariationId is 776598.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016352.4. 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
	CPA4	NM_016352.4	MANE Select	c.777G>A	p.Trp259*	stop_gained	Exon 8 of 11	NP_057436.2	A4D1M3
	CPA4	NM_001163446.2		c.678G>A	p.Trp226*	stop_gained	Exon 7 of 10	NP_001156918.1	Q9UI42-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPA4	ENST00000222482.10	TSL:1 MANE Select	c.777G>A	p.Trp259*	stop_gained	Exon 8 of 11	ENSP00000222482.4	Q9UI42-1
	CPA4	ENST00000445470.6	TSL:2	c.678G>A	p.Trp226*	stop_gained	Exon 7 of 10	ENSP00000412947.2	Q9UI42-2
	CPA4	ENST00000493259.5	TSL:2	c.465G>A	p.Trp155*	stop_gained	Exon 6 of 9	ENSP00000419660.1	B7Z5J4

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

GnomAD2 exomes AF: 0.00234 AC: 588 AN: 251442 AF XY: 0.00254

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 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

African (AFR) AF: 0.000627 AC: 21 AN: 33478

American (AMR) AF: 0.00145 AC: 65 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 105 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00238 AC: 205 AN: 86254

European-Finnish (FIN) AF: 0.000861 AC: 46 AN: 53418

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00433 AC: 4814 AN: 1111886

Other (OTH) AF: 0.00315 AC: 190 AN: 60394

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

African (AFR) AF: 0.000818 AC: 34 AN: 41566

American (AMR) AF: 0.00261 AC: 40 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4822

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00385 AC: 262 AN: 68028

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00346 Hom.: 4

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CPA4-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.1
Vest4		0.27
GERP RS		5.8
Mutation Taster		=35/165	disease causing (fs/PTC)

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

Other links and lift over

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