rs794727334

Variant names:

• chr13-100449305-GGTAA-G
• rs794727334
• NM_000282.4:c.1899+4_1899+7delAGTA

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

The NM_000282.4(PCCA):​c.1899+4_1899+7delAGTA variant causes a splice 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_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.98
• Publications: 4 publications found

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]

PCCA Gene-Disease associations (from GenCC):

• propionic acidemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PP3: Splicing predictors support a deleterious 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 195560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCA	NM_000282.4	c.1899+4_1899+7delAGTA		splice_region_variant, intron_variant	Intron 21 of 23	ENST00000376285.6	NP_000273.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCA	ENST00000376285.6	c.1899+1_1899+4delGTAA		splice_donor_variant, splice_region_variant, intron_variant	Intron 21 of 23	1	NM_000282.4	ENSP00000365462.1

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

GnomAD2 exomes AF: 0.0000590 AC: 9 AN: 152424 AF XY: 0.0000623

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 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

African (AFR) AF: 0.00 AC: 0 AN: 30762

American (AMR) AF: 0.000198 AC: 7 AN: 35428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24898

East Asian (EAS) AF: 0.00 AC: 0 AN: 35476

South Asian (SAS) AF: 0.00 AC: 0 AN: 77878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 0.0000135 AC: 14 AN: 1040862

Other (OTH) AF: 0.00 AC: 0 AN: 56550

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

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00125 AC: 19 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

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

Aug 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 24, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 26, 2020

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 30, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Dec 02, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs794727334; hg19: chr13-101101559;