Genetic Variant NM_000282.4:c.12C>A (chr13-100089132-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000282.4(PCCA):c.12C>A(p.Phe4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000739 in 1,353,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F4F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

PCCA
NM_000282.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.984

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08028415).

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.12C>A	p.Phe4Leu	missense	Exon 1 of 24	NP_000273.2	P05165-1
PCCA	NM_001352610.2		c.-855C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	NP_001339539.1
PCCA	NM_001352611.2		c.-855C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 22	NP_001339540.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCCA	ENST00000376285.6	TSL:1 MANE Select	c.12C>A	p.Phe4Leu	missense	Exon 1 of 24	ENSP00000365462.1	P05165-1
PCCA	ENST00000881637.1		c.12C>A	p.Phe4Leu	missense	Exon 1 of 25	ENSP00000551696.1
PCCA	ENST00000881640.1		c.12C>A	p.Phe4Leu	missense	Exon 1 of 25	ENSP00000551699.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.39e-7

AC:

AN:

1353966

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

664768

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:

AN:

28558

American (AMR)

AF:

0.00

AC:

AN:

32808

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23638

East Asian (EAS)

AF:

0.0000307

AC:

AN:

32582

South Asian (SAS)

AF:

0.00

AC:

AN:

73078

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4774

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1057212

Other (OTH)

AF:

0.00

AC:

AN:

55962

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

0.34

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.32

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.0073

LIST_S2

Benign

0.49

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.080

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

-0.34

PhyloP100

-0.98

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.32

REVEL

Uncertain

0.29

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.15

MutPred

0.23

Loss of catalytic residue at F4 (P = 0.064)

MVP

0.56

MPC

0.16

ClinPred

0.057

GERP RS

-5.8

PromoterAI

-0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.040

gMVP

0.14

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over