rs111778723

chr13-100111820-ATG-Achr13-100111820-ATG-ATGTG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000282.4(PCCA):c.184-17_184-16del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,563,578 control chromosomes in the GnomAD database, including 9,092 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1214 hom., cov: 30)
  • Exomes 𝑓: 0.10 (7878 hom.)
• Consequence: PCCA NM_000282.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.885

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 13-100111820-ATG-A is Benign according to our data. Variant chr13-100111820-ATG-A is described in ClinVar as [Benign]. Clinvar id is 196244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100111820-ATG-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCCA	NM_000282.4	c.184-17_184-16del		intron_variant		ENST00000376285.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCCA	ENST00000376285.6	c.184-17_184-16del		intron_variant		1	NM_000282.4	P1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17897 AN: 151908 Hom.: 1212 Cov.: 30

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0589

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.132

GnomAD3 exomes AF: 0.0929 AC: 22682 AN: 244140 Hom.: 1230 AF XY: 0.0949 AC XY: 12515 AN XY: 131902

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.0699

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.000443

Gnomad SAS exome AF: 0.114

Gnomad FIN exome AF: 0.0564

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.0995 AC: 140483 AN: 1411550 Hom.: 7878 AF XY: 0.0997 AC XY: 70282 AN XY: 704592

Gnomad4 AFR exome AF: 0.183

Gnomad4 AMR exome AF: 0.0734

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.000534

Gnomad4 SAS exome AF: 0.113

Gnomad4 FIN exome AF: 0.0579

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.108

GnomAD4 genome AF: 0.118 AC: 17933 AN: 152028 Hom.: 1214 Cov.: 30 AF XY: 0.115 AC XY: 8560 AN XY: 74326

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.128

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.0589

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.131

Alfa AF: 0.114 Hom.: 194

Bravo AF: 0.123

Asia WGS AF: 0.0570 AC: 196 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 17, 2019	Variant summary: PCCA c.184-17_184-16delGT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.093 in 244140 control chromosomes in the gnomAD database, including 1230 homozygotes. The observed variant frequency is approximately 27-folds over the estimated maximal expected allele frequency for a pathogenic variant in PCCA causing Propionic Acidemia phenotype (0.0034), strongly suggesting that the variant is benign. Two ClinVar submissions (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 02, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, flagged submission	clinical testing	GeneDx	Apr 04, 2014	The variant is found in UCD-MET panel(s). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Propionic acidemia Benign:4

Benign, criteria provided, single submitter	research	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jan 01, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Computational scores

Source: dbNSFP v4.3

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: rs111778723; hg19: chr13-100764074;