rs781030239

Variant names:

• chr13-100089188-AGCAGCTGATG-A
• rs781030239
• NM_000282.4:c.69_78delGCAGCTGATG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000282.4(PCCA):​c.69_78delGCAGCTGATG​(p.Gln23HisfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000029 in 1,376,952 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q23Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: PCCA NM_000282.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.34
• Publications: 1 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 202 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-100089188-AGCAGCTGATG-A is Pathogenic according to our data. Variant chr13-100089188-AGCAGCTGATG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 556623.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCA	NM_000282.4	MANE Select	c.69_78delGCAGCTGATG	p.Gln23HisfsTer2	frameshift	Exon 1 of 24	NP_000273.2	P05165-1
	PCCA	NM_001352605.2		c.69_78delGCAGCTGATG	p.Gln23HisfsTer2	frameshift	Exon 1 of 23	NP_001339534.1
	PCCA	NM_001127692.3		c.69_78delGCAGCTGATG	p.Gln23HisfsTer2	frameshift	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.69_78delGCAGCTGATG	p.Gln23HisfsTer2	frameshift	Exon 1 of 24	ENSP00000365462.1	P05165-1
	PCCA	ENST00000881637.1		c.69_78delGCAGCTGATG	p.Gln23HisfsTer2	frameshift	Exon 1 of 25	ENSP00000551696.1
	PCCA	ENST00000881640.1		c.69_78delGCAGCTGATG	p.Gln23HisfsTer2	frameshift	Exon 1 of 25	ENSP00000551699.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 138294 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000290 AC: 4 AN: 1376952 Hom.: 0 AF XY: 0.00000442 AC XY: 3 AN XY: 678222

African (AFR) AF: 0.00 AC: 0 AN: 29284

American (AMR) AF: 0.00 AC: 0 AN: 35072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24440

East Asian (EAS) AF: 0.00 AC: 0 AN: 33912

South Asian (SAS) AF: 0.00 AC: 0 AN: 75386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4170

European-Non Finnish (NFE) AF: 0.00000373 AC: 4 AN: 1072056

Other (OTH) AF: 0.00 AC: 0 AN: 57104

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Propionic acidemia (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs781030239; hg19: chr13-100741442;