13-100089226-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000282.4(PCCA):​c.105+1G>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Consequence

PCCA
NM_000282.4 splice_donor, intron

Scores

3
2
2
Splicing: ADA: 1.000
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.40
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-100089226-G-C is Pathogenic according to our data. Variant chr13-100089226-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2677509.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PCCANM_000282.4 linkc.105+1G>C splice_donor_variant, intron_variant Intron 1 of 23 ENST00000376285.6 NP_000273.2 P05165-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PCCAENST00000376285.6 linkc.105+1G>C splice_donor_variant, intron_variant Intron 1 of 23 1 NM_000282.4 ENSP00000365462.1 P05165-1
PCCAENST00000376286.8 linkc.105+1G>C splice_donor_variant, intron_variant Intron 1 of 22 2 ENSP00000365463.4 P05165-2
PCCAENST00000376279.7 linkc.105+1G>C splice_donor_variant, intron_variant Intron 1 of 22 2 ENSP00000365456.3 P05165-3
PCCAENST00000647303.1 linkn.105+1G>C splice_donor_variant, intron_variant Intron 1 of 20 ENSP00000495663.1 A0A2R8Y725

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Propionic acidemia Pathogenic:1
Aug 31, 2022
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Uncertain
0.11
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Benign
0.72
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.9

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.21
Position offset: 23
DS_DL_spliceai
1.0
Position offset: -1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-100741480; API