GeneBe

chr13-100262786-ACTAAT-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000376285.6(PCCA):​c.775_779delCTAAT​(p.Leu259ArgfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,576,204 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L259L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000098 ( 0 hom. )

Consequence

PCCA
ENST00000376285.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.61

Publications

0 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-100262786-ACTAAT-A is Pathogenic according to our data. Variant chr13-100262786-ACTAAT-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 193576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000376285.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
PCCA
NM_000282.4
MANE Select
c.775_779delCTAATp.Leu259ArgfsTer5
frameshift
Exon 10 of 24NP_000273.2
PCCA
NM_001352605.2
c.775_779delCTAATp.Leu259ArgfsTer5
frameshift
Exon 10 of 23NP_001339534.1
PCCA
NM_001127692.3
c.697_701delCTAATp.Leu233ArgfsTer5
frameshift
Exon 9 of 23NP_001121164.1

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
PCCA
ENST00000376285.6
TSL:1 MANE Select
c.775_779delCTAATp.Leu259ArgfsTer5
frameshift
Exon 10 of 24ENSP00000365462.1
PCCA
ENST00000376286.8
TSL:2
c.697_701delCTAATp.Leu233ArgfsTer5
frameshift
Exon 9 of 23ENSP00000365463.4
PCCA
ENST00000376279.7
TSL:2
c.775_779delCTAATp.Leu259ArgfsTer5
frameshift
Exon 10 of 23ENSP00000365456.3

Frequencies

GnomAD3 genomes
AF:
0.0000198
AC:
3
AN:
151462
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000983
AC:
14
AN:
1424742
Hom.:
0
AF XY:
0.0000127
AC XY:
9
AN XY:
711074
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
32810
American (AMR)
AF:
0.00
AC:
0
AN:
44648
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25894
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39434
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84746
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52846
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5682
European-Non Finnish (NFE)
AF:
0.0000130
AC:
14
AN:
1079614
Other (OTH)
AF:
0.00
AC:
0
AN:
59068
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000303245), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.382
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000198
AC:
3
AN:
151462
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
73888
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41146
American (AMR)
AF:
0.00
AC:
0
AN:
15178
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5148
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4800
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10432
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000441
AC:
3
AN:
67976
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.442
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000264

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts
View on ClinVar
Pathogenic
VUS
Benign
Condition
4
-
-
Propionic acidemia (4)
1
-
-
not provided (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
8.6
Mutation Taster
=1/199
disease causing (ClinVar)

Splicing

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

Publications

Other links and lift over

dbSNP: rs794726976; hg19: chr13-100915040; API