rs764045674

chr13-100307261-GTTAGT-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_000282.4(PCCA):c.1353+5_1353+9del variant causes a splice donor, splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000042 in 1,429,704 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: PCCA NM_000282.4 splice_donor, splice_donor_5th_base, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.21

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.03109282 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-100307261-GTTAGT-G is Pathogenic according to our data. Variant chr13-100307261-GTTAGT-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 254165.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCCA	NM_000282.4	c.1353+5_1353+9del		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		ENST00000376285.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCCA	ENST00000376285.6	c.1353+5_1353+9del		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		1	NM_000282.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250478 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135434

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000420 AC: 6 AN: 1429704 Hom.: 0 AF XY: 0.00000561 AC XY: 4 AN XY: 713318

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000467

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.23e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Propionic acidemia Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 15, 2023	- -
Pathogenic, criteria provided, single submitter	research	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jan 01, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change falls in intron 15 of the PCCA gene. It does not directly change the encoded amino acid sequence of the PCCA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs764045674, gnomAD 0.01%). This variant has been observed in individual(s) with propionic acidemia (PMID: 25636094, 27227689). ClinVar contains an entry for this variant (Variation ID: 254165). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, criteria provided, single submitter	in vitro;research	Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics	Feb 17, 2021	PS3, PM2, PM3_supportive, PP3, PP4 -

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: rs764045674; hg19: chr13-100959515;