rs192171304

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3PM2PP5_Very_Strong

The NM_000282.4(PCCA):c.1746G>A(p.Ser582Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000127 in 1,571,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001362339: "These predictions are supported by a functional study that reported an impact on mRNA splicing (Yang_2004)."" and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

PCCA
NM_000282.4 splice_region, synonymous

Scores

Splicing: ADA: 0.9379

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: -0.459

Publications

7 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: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P

PCCA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001362339: "These predictions are supported by a functional study that reported an impact on mRNA splicing (Yang_2004)."; SCV002231975: Studies have shown that this variant results in skipping of exon 19 and introduces a premature termination codon (PMID: 15059621).; SCV006584979: "Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product." PMID: 15059621; SCV004710652: This variant results in skipping of exon 19 (Yang et al. 2004. PubMed ID: 15059621).

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-100368574-G-A is Pathogenic according to our data. Variant chr13-100368574-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 556480.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	UniProt
PCCA	NM_000282.4	MANE Select	c.1746G>A	p.Ser582Ser	splice_region synonymous	Exon 19 of 24	NP_000273.2	P05165-1
PCCA	NM_001352605.2		c.1746G>A	p.Ser582Ser	splice_region synonymous	Exon 19 of 23	NP_001339534.1
PCCA	NM_001127692.3		c.1668G>A	p.Ser556Ser	splice_region synonymous	Exon 18 of 23	NP_001121164.1	P05165-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCCA	ENST00000376285.6	TSL:1 MANE Select	c.1746G>A	p.Ser582Ser	splice_region synonymous	Exon 19 of 24	ENSP00000365462.1	P05165-1
PCCA	ENST00000881637.1		c.1869G>A	p.Ser623Ser	splice_region synonymous	Exon 20 of 25	ENSP00000551696.1
PCCA	ENST00000881640.1		c.1851G>A	p.Ser617Ser	splice_region synonymous	Exon 20 of 25	ENSP00000551699.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151292

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251064

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000127

AC:

AN:

1419678

Hom.:

Cov.:

AF XY:

0.0000197

AC XY:

AN XY:

709150

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32420

American (AMR)

AF:

0.00

AC:

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25852

East Asian (EAS)

AF:

0.00

AC:

AN:

39290

South Asian (SAS)

AF:

0.000129

AC:

AN:

85356

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00000372

AC:

AN:

1074140

Other (OTH)

AF:

0.0000509

AC:

AN:

58916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.0000132

AC:

AN:

151408

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73900

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41278

American (AMR)

AF:

0.0000657

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.00

AC:

AN:

4754

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10426

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67846

Other (OTH)

AF:

0.00

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00

Hom.:

Bravo

AF:

0.0000416

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Propionic acidemia (5)

PCCA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.43

PhyloP100

-0.46

PromoterAI

-0.081

Neutral

(source)

Mutation Taster

=80/20

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.94

dbscSNV1_RF

Pathogenic

0.89

SpliceAI score (max)

0.47

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.30

Position offset: -13

DS_DL_spliceai

0.47

Position offset: 0

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.

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

Computational scores

Splicing

Publications

Other links and lift over