rs781030239

Positions:

• chr13-100089188-AGCAGCTGATG-A

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.69_78del​(p.Gln23HisfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000029 in 1,376,952 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q23Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: PCCA NM_000282.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.34

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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 145 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-100089188-AGCAGCTGATG-A is Pathogenic according to our data. Variant chr13-100089188-AGCAGCTGATG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556623.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.69_78del	p.Gln23HisfsTer2	frameshift_variant	1/24	ENST00000376285.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCCA	ENST00000376285.6	c.69_78del	p.Gln23HisfsTer2	frameshift_variant	1/24	1	NM_000282.4	P1
PCCA	ENST00000376279.7	c.69_78del	p.Gln23HisfsTer2	frameshift_variant	1/23	2
PCCA	ENST00000376286.8	c.69_78del	p.Gln23HisfsTer2	frameshift_variant	1/23	2
PCCA	ENST00000647303.1	c.69_78del	p.Gln23HisfsTer2	frameshift_variant, NMD_transcript_variant	1/21

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000290 AC: 4 AN: 1376952 Hom.: 0 AF XY: 0.00000442 AC XY: 3 AN XY: 678222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000373

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Propionic acidemia Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 16, 2023	ClinVar contains an entry for this variant (Variation ID: 556623). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with propionic aciduria (PMID: 27489777). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln23Hisfs*2) 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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 15, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 26, 2023	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs781030239; hg19: chr13-100741442;