13-100089140-G-C

Position:

• chr13-100089140-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000282.4(PCCA):​c.20G>C​(p.Gly7Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,369,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: PCCA NM_000282.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17763266).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCCA	NM_000282.4	c.20G>C	p.Gly7Ala	missense_variant	1/24	ENST00000376285.6	NP_000273.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCCA	ENST00000376285.6	c.20G>C	p.Gly7Ala	missense_variant	1/24	1	NM_000282.4	ENSP00000365462	P1
PCCA	ENST00000376286.8	c.20G>C	p.Gly7Ala	missense_variant	1/23	2		ENSP00000365463
PCCA	ENST00000376279.7	c.20G>C	p.Gly7Ala	missense_variant	1/23	2		ENSP00000365456
PCCA	ENST00000647303.1	c.20G>C	p.Gly7Ala	missense_variant, NMD_transcript_variant	1/21			ENSP00000495663

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000723 AC: 1 AN: 138342 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 75010

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000187

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1369992 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 674402

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.37e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000112 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Propionic acidemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 7 of the PCCA protein (p.Gly7Ala). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with PCCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 1994290). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PCCA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	14
DANN	Benign	0.46
DEOGEN2	Benign	0.34	.;.;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.83	T;T;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.55	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.030	N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.80	T;T;T
Polyphen		0.030	B;.;B
Vest4		0.34
MutPred		0.32		Gain of MoRF binding (P = 0.118);Gain of MoRF binding (P = 0.118);Gain of MoRF binding (P = 0.118);
MVP		0.74
MPC		0.16
ClinPred		0.11	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.51

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

LitVar

Other links and lift over

dbSNP: rs1283043748; hg19: chr13-100741394;