NM_000282.4:c.20G>C

Variant names:

• chr13-100089140-G-C
• rs1283043748
• NM_000282.4:c.20G>C

Variant summary

Our verdict is Uncertain significance. The variant received 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G7R) has been classified 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
• Publications: 0 publications found

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

ACMG classification

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=0.17763266).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCA	NM_000282.4	MANE Select	c.20G>C	p.Gly7Ala	missense	Exon 1 of 24	NP_000273.2	P05165-1
	PCCA	NM_001352605.2		c.20G>C	p.Gly7Ala	missense	Exon 1 of 23	NP_001339534.1
	PCCA	NM_001127692.3		c.20G>C	p.Gly7Ala	missense	Exon 1 of 23	NP_001121164.1	P05165-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCA	ENST00000376285.6	TSL:1 MANE Select	c.20G>C	p.Gly7Ala	missense	Exon 1 of 24	ENSP00000365462.1	P05165-1
	PCCA	ENST00000881637.1		c.20G>C	p.Gly7Ala	missense	Exon 1 of 25	ENSP00000551696.1
	PCCA	ENST00000881640.1		c.20G>C	p.Gly7Ala	missense	Exon 1 of 25	ENSP00000551699.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000723 AC: 1 AN: 138342 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 29130

American (AMR) AF: 0.00 AC: 0 AN: 34482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23992

East Asian (EAS) AF: 0.00 AC: 0 AN: 33502

South Asian (SAS) AF: 0.00 AC: 0 AN: 74692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4692

European-Non Finnish (NFE) AF: 9.37e-7 AC: 1 AN: 1067300

Other (OTH) AF: 0.00 AC: 0 AN: 56770

GnomAD4 genome Cov.: 33

Alfa AF: 0.000112 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Propionic acidemia (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.030	N
REVEL	Uncertain	0.31
Sift	Benign	0.22	T
Sift4G	Benign	0.80	T
Polyphen		0.030	B
Vest4		0.34
MutPred		0.32		Gain of MoRF binding (P = 0.118)
MVP		0.74
MPC		0.16
ClinPred		0.11	T
GERP RS		3.9
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.51
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs1283043748; hg19: chr13-100741394;