Genetic Variant PCCA:p.Met1? (chr13-100089122-T-A) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000282.4(PCCA):c.2T>A(p.Met1?) variant causes a start lost 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. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PCCA
NM_000282.4 start_lost

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.72

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 links:

PCCA-DT (HGNC:53266): (PCCA divergent transcript)

PCCA-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 11 pathogenic variants. Next in-frame start position is after 26 codons. Genomic position: 100089196. Lost 0.035 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-100089122-T-A is Pathogenic according to our data. Variant chr13-100089122-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 638018.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCA	NM_000282.4 link	c.2T>A	p.Met1?	start_lost	Exon 1 of 24	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.2T>A	p.Met1?	start_lost	Exon 1 of 24	1	NM_000282.4	ENSP00000365462.1		P05165-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1344726

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

659086

African (AFR)

AF:

0.00

AC:

AN:

28258

American (AMR)

AF:

0.00

AC:

AN:

31758

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23438

East Asian (EAS)

AF:

0.00

AC:

AN:

32118

South Asian (SAS)

AF:

0.00

AC:

AN:

71812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4926

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1051384

Other (OTH)

AF:

0.00

AC:

AN:

55496

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Propionic acidemia

Pathogenic:1

May 08, 2019

Laboratory of Metabolic Disorders, Peking University First Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.62

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.38

.;.;T

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

PhyloP100

2.7

PROVEAN

Benign

-1.6

N;N;N

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.81

P;.;P

Vest4

0.85

MutPred

0.97

Gain of MoRF binding (P = 0.0086);Gain of MoRF binding (P = 0.0086);Gain of MoRF binding (P = 0.0086);

MVP

0.99

ClinPred

1.0

GERP RS

4.8

PromoterAI

-0.63

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.72

Mutation Taster

=11/189

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over