NM_000282.4:c.1855C>T

Variant names:

• chr13-100449261-C-T
• rs1194679272
• NM_000282.4:c.1855C>T

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.1855C>T​(p.Arg619*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000649 in 1,386,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: PCCA NM_000282.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.94
• Publications: 2 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 Gene-Disease associations (from GenCC):

• propionic acidemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-100449261-C-T is Pathogenic according to our data. Variant chr13-100449261-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 553941.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.1855C>T	p.Arg619*	stop_gained	Exon 21 of 24	NP_000273.2	P05165-1
	PCCA	NM_001127692.3		c.1777C>T	p.Arg593*	stop_gained	Exon 20 of 23	NP_001121164.1	P05165-2
	PCCA	NM_001178004.2		c.1855C>T	p.Arg619*	stop_gained	Exon 21 of 23	NP_001171475.1	P05165-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCA	ENST00000376285.6	TSL:1 MANE Select	c.1855C>T	p.Arg619*	stop_gained	Exon 21 of 24	ENSP00000365462.1	P05165-1
	PCCA	ENST00000881637.1		c.1978C>T	p.Arg660*	stop_gained	Exon 22 of 25	ENSP00000551696.1
	PCCA	ENST00000881640.1		c.1960C>T	p.Arg654*	stop_gained	Exon 22 of 25	ENSP00000551699.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000130 AC: 2 AN: 153426 AF XY: 0.0000247

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: 0.00000649 AC: 9 AN: 1386042 Hom.: 0 Cov.: 26 AF XY: 0.00000730 AC XY: 5 AN XY: 684480

African (AFR) AF: 0.00 AC: 0 AN: 31326

American (AMR) AF: 0.00 AC: 0 AN: 35608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25080

East Asian (EAS) AF: 0.00 AC: 0 AN: 35608

South Asian (SAS) AF: 0.0000381 AC: 3 AN: 78824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00000562 AC: 6 AN: 1067218

Other (OTH) AF: 0.00 AC: 0 AN: 57458

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Propionic acidemia (4)
1	-	-	not provided (1)
1	-	-	PCCA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		3.9
Vest4		0.93
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1194679272; hg19: chr13-101101515;