3-148868988-A-G

Position:

• chr3-148868988-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001870.4(CPA3):​c.218A>G​(p.Lys73Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPA3 NM_001870.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.44

Genes affected

CPA3 (HGNC:2298): (carboxypeptidase A3) This gene encodes a member of the carboxypeptidase A family of zinc metalloproteases. The encoded preproprotein is proteolytically processed to generate a mature protease that is released by mast cells and may be involved in the degradation of endogenous proteins and the inactivation of venom-associated peptides. Expression of this gene may be elevated in human asthma patients. [provided by RefSeq, Nov 2015]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17346242).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPA3	NM_001870.4	c.218A>G	p.Lys73Arg	missense_variant	3/11	ENST00000296046.4	NP_001861.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPA3	ENST00000296046.4	c.218A>G	p.Lys73Arg	missense_variant	3/11	1	NM_001870.4	ENSP00000296046	P1
	ENST00000488190.1	n.304+960T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

May 13, 2024

The c.218A>G (p.K73R) alteration is located in exon 3 (coding exon 3) of the CPA3 gene. This alteration results from a A to G substitution at nucleotide position 218, causing the lysine (K) at amino acid position 73 to be replaced by an arginine (R). 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	0.088
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.029
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.66	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.088
Sift	Benign	0.18	T
Sift4G	Benign	0.48	T
Polyphen		0.093	B
Vest4		0.27
MutPred		0.40		Loss of ubiquitination at K73 (P = 0.0183);
MVP		0.47
MPC		0.042
ClinPred		0.60	D
GERP RS		5.5
Varity_R		0.19
gMVP		0.24

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-148586775; COSMIC: COSV56045761;