rs794727334

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The ENST00000376285.6(PCCA):c.1899+1_1899+4delGTAA variant causes a splice donor, 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
ENST00000376285.6 splice_donor, splice_region, intron

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.98

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.024691358 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;

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 rank	MANE	Protein	UniProt
PCCA	NM_000282.4 link	c.1899+4_1899+7delAGTA		splice_region_variant, intron_variant	Intron 21 of 23	ENST00000376285.6	NP_000273.2	P05165-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCA	ENST00000376285.6 link	c.1899+1_1899+4delGTAA		splice_donor_variant, splice_region_variant, intron_variant	Intron 21 of 23	1	NM_000282.4	ENSP00000365462.1		P05165-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

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:

AN:

152424

Hom.:

AF XY:

0.0000623

AC XY:

AN XY:

80316

show subpopulations

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:

AN:

1356648

Hom.:

AF XY:

0.0000179

AC XY:

AN XY:

671598

show subpopulations

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:

AN:

152052

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74258

show subpopulations

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

LINK: link

Submissions by phenotype

Propionic acidemia

Pathogenic:6

Mar 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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. -

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. -

Mar 30, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over