rs794727334

chr13-100449305-GGTAA-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1_Moderate PM2 PP3 PP5_Very_Strong

The NM_000282.4(PCCA):c.1899+4_1899+7del variant causes a splice donor, splice donor region, intron change. The variant allele was found at a frequency of 0.0000278 in 1,508,700 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: PCCA NM_000282.4 splice_donor, splice_donor_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.98

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 13 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.02423411 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.3, offset of 0 (no position change), new splice context is: gtgGTatga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-100449305-GGTAA-G is Pathogenic according to our data. Variant chr13-100449305-GGTAA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 195560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100449305-GGTAA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCCA	NM_000282.4	c.1899+4_1899+7del		splice_donor_variant, splice_donor_region_variant, intron_variant		ENST00000376285.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCCA	ENST00000376285.6	c.1899+4_1899+7del		splice_donor_variant, splice_donor_region_variant, intron_variant		1	NM_000282.4	P1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152052 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000590 AC: 9 AN: 152424 Hom.: 0 AF XY: 0.0000623 AC XY: 5 AN XY: 80316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000288

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000173

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.0000155 AC: 21 AN: 1356648 Hom.: 0 AF XY: 0.0000179 AC XY: 12 AN XY: 671598

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000198

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: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152052 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74258

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Propionic acidemia Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jun 26, 2020	This variant is a 4 bp deletion starting at position +4 of intron 21 of the PCCA gene and is predicted to affect native splicing by in-silico tools. This variant, named 1824IVS+3del4, has been previously reported as a homozygous change in an individual with propionic acidemia and moderate psychomotor delay (PMID: 10780784, 9385377). The PCC enzyme activity in the patient's fibroblasts was significantly lower than the normal control (PMID: 10780784). The c.1899+4_1899+7del is also reported in the literature as IVS21+3del4 (PMID: 15235904). Splicing studies in patient's fibroblasts demonstrated that this variant leads to skipping of exon 21 and residual low levels of normal splicing (PMID: 9385377, 15235904). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0059% (9/152424) and thus is presumed to be rare. Based on the available evidence, the c.1899+4_1899+7del variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 24, 2022	Variant summary: PCCA c.1899+4_1899+7delAGTA alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. At least one publication reports experimental evidence that this variant affects mRNA splicing. In functional studies, the variant resulted in an in-frame deletion of 18 amino acids as a result of exon skipping (Richard_1997, Clavero_2004). It was also reported that small levels of (3-16%) of correctly spliced transcript were found in a homozygous patient, which was sufficient to permit the development of a mild phenotype (Clavero_2004). The variant allele was found at a frequency of 5.9e-05 in 152424 control chromosomes (gnomAD). c.1899+4_1899+7delAGTA has been reported in the literature in multiple individuals affected with Propionic Acidemia (Richard_1997, Kraus_2012, Stanescu_2021). These data indicate that the variant is very likely to be associated with disease. Two assessments for this variant have been submitted to ClinVar after 2014. One submitter classified the variant as pathogenic and the other classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	This sequence change falls in intron 21 of the PCCA gene. It does not directly change the encoded amino acid sequence of the PCCA protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs794727334, gnomAD 0.03%). This variant has been observed in individual(s) with propionic acidemia (PMID: 9385377, 10101253, 10780784, 22033733). This variant is also known as 1824IVS+3del4 and IVS21+3del4. ClinVar contains an entry for this variant (Variation ID: 195560). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of 21, but is expected to preserve the integrity of the reading-frame (PMID: 9385377, 15235904). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 29, 2022	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 02, 2014

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.75		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs794727334; hg19: chr13-101101559;