rs745571507

Positions:

• chr13-100262732-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000282.4(PCCA):​c.722del​(p.Gly241ValfsTer19) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 1,477,148 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: PCCA NM_000282.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.23

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-100262732-TG-T is Pathogenic according to our data. Variant chr13-100262732-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCCA	NM_000282.4	c.722del	p.Gly241ValfsTer19	frameshift_variant	10/24	ENST00000376285.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCCA	ENST00000376285.6	c.722del	p.Gly241ValfsTer19	frameshift_variant	10/24	1	NM_000282.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000335 AC: 5 AN: 149044 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000320 AC: 8 AN: 249684 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135180

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 21 AN: 1328104 Hom.: 0 Cov.: 25 AF XY: 0.0000195 AC XY: 13 AN XY: 666248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000669

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.98e-7

Gnomad4 OTH exome AF: 0.0000552

GnomAD4 genome AF: 0.0000335 AC: 5 AN: 149044 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 2 AN XY: 72728

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Propionic acidemia Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 05, 2018	Variant summary: The PCCA c.722delG (p.Gly241ValfsX19) variant results in a premature termination codon, predicted to cause a truncated or absent PCCA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 8/245002 control chromosomes in gnomAD at a frequency of 0.0000327, which does not exceed the estimated maximal expected allele frequency of a pathogenic PCCA variant (0.003446). This variant has been identified in at least 2 patients with Propionic Acidemia, both of whom were homozygous and had early onset of symptoms (Perez_2003, Tuchman_2008). Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	This sequence change creates a premature translational stop signal (p.Gly241Valfs*19) in the PCCA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCCA are known to be pathogenic (PMID: 15464417). This variant is present in population databases (rs745571507, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with propionic acidemia (PMID: 12559849). ClinVar contains an entry for this variant (Variation ID: 551231). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 04, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 02, 2024	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs745571507; hg19: chr13-100914986;