Variant summary

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

The NM_000282.4(PCCA):c.722delG(p.Gly241ValfsTer19) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 1,477,148 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000034 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

PCCA
NM_000282.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.23

Publications

1 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

PCCA links:

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 13-100262732-TG-T is Pathogenic according to our data. Variant chr13-100262732-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 551231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000282.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCCA	NM_000282.4	MANE Select	c.722delG	p.Gly241ValfsTer19	frameshift	Exon 10 of 24	NP_000273.2
PCCA	NM_001352605.2		c.722delG	p.Gly241ValfsTer19	frameshift	Exon 10 of 23	NP_001339534.1
PCCA	NM_001127692.3		c.644delG	p.Gly215ValfsTer19	frameshift	Exon 9 of 23	NP_001121164.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCCA	ENST00000376285.6	TSL:1 MANE Select	c.722delG	p.Gly241ValfsTer19	frameshift	Exon 10 of 24	ENSP00000365462.1
PCCA	ENST00000881637.1		c.845delG	p.Gly282ValfsTer19	frameshift	Exon 11 of 25	ENSP00000551696.1
PCCA	ENST00000881640.1		c.827delG	p.Gly276ValfsTer19	frameshift	Exon 11 of 25	ENSP00000551699.1

Frequencies

GnomAD3 genomes

AF:

0.0000335

AC:

AN:

149044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00116

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000320

AC:

AN:

249684

AF XY:

0.0000296

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000696

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1328104

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

666248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30440

American (AMR)

AF:

0.00

AC:

AN:

43292

Ashkenazi Jewish (ASJ)

AF:

0.000669

AC:

AN:

23914

East Asian (EAS)

AF:

0.00

AC:

AN:

35990

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5340

European-Non Finnish (NFE)

AF:

9.98e-7

AC:

AN:

1002186

Other (OTH)

AF:

0.0000552

AC:

AN:

54314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000335

AC:

AN:

149044

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

72728

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40582

American (AMR)

AF:

0.00

AC:

AN:

14888

Ashkenazi Jewish (ASJ)

AF:

0.00116

AC:

AN:

3446

East Asian (EAS)

AF:

0.00

AC:

AN:

4858

South Asian (SAS)

AF:

0.00

AC:

AN:

4410

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10212

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67372

Other (OTH)

AF:

0.00

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000130

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Propionic acidemia (7)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.2

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs745571507

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over