rs538229

Positions:

• chr13-100235868-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000282.4(PCCA):​c.627A>G​(p.Ala209Ala) variant causes a synonymous change. The variant allele was found at a frequency of 0.163 in 1,601,178 control chromosomes in the GnomAD database, including 22,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1677 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21110 hom.)
• Consequence: PCCA NM_000282.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 5.13

Genes affected

PCCA (HGNC:8653): (propionyl-CoA carboxylase subunit alpha) The protein encoded by this gene is the alpha subunit of the heterodimeric mitochondrial enzyme Propionyl-CoA carboxylase. PCCA encodes the biotin-binding region of this enzyme. Mutations in either PCCA or PCCB (encoding the beta subunit) lead to an enzyme deficiency resulting in propionic acidemia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

PCCA (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 13-100235868-A-G is Benign according to our data. Variant chr13-100235868-A-G is described in ClinVar as [Benign]. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCCA	NM_000282.4	c.627A>G	p.Ala209Ala	synonymous_variant	8/24	ENST00000376285.6	NP_000273.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCCA	ENST00000376285.6	c.627A>G	p.Ala209Ala	synonymous_variant	8/24	1	NM_000282.4	ENSP00000365462.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21555 AN: 152104 Hom.: 1677 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.0917

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.146

GnomAD3 exomes AF: 0.147 AC: 37067 AN: 251336 Hom.: 3107 AF XY: 0.150 AC XY: 20341 AN XY: 135830

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.00870

Gnomad SAS exome AF: 0.151

Gnomad FIN exome AF: 0.0961

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.165 AC: 239420 AN: 1448956 Hom.: 21110 Cov.: 27 AF XY: 0.165 AC XY: 119037 AN XY: 721788

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.167

Gnomad4 ASJ exome AF: 0.173

Gnomad4 EAS exome AF: 0.00614

Gnomad4 SAS exome AF: 0.151

Gnomad4 FIN exome AF: 0.103

Gnomad4 NFE exome AF: 0.177

Gnomad4 OTH exome AF: 0.158

GnomAD4 genome AF: 0.142 AC: 21567 AN: 152222 Hom.: 1677 Cov.: 32 AF XY: 0.137 AC XY: 10167 AN XY: 74424

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.160

Gnomad4 ASJ AF: 0.155

Gnomad4 EAS AF: 0.0112

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.0917

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.146

Alfa AF: 0.169 Hom.: 1498

Bravo AF: 0.147

Asia WGS AF: 0.0800 AC: 277 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 11, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Propionic acidemia Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2017	Variant summary: The PCCA c.627A>G (p.Ala209Ala) variant involves the alteration of a conserved nucleotide causing a synonymous change that 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 17901/121368 control chromosomes (1483 homozygotes) at a frequency of 0.1474936, which is approximately 43 times the estimated maximal expected allele frequency for a pathogenic PCCA variant (0.003446), strong evidence that this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs538229; hg19: chr13-100888122; COSMIC: COSV66191930;