chr13-100089226-G-A

Variant names:

• chr13-100089226-G-A
• rs879253804
• NM_000282.4:c.105+1G>A

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.105+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000221 in 1,357,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: PCCA NM_000282.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.40
• 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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-100089226-G-A is Pathogenic according to our data. Variant chr13-100089226-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 218251.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.105+1G>A		splice_donor intron	N/A	NP_000273.2	P05165-1
	PCCA	NM_001352605.2		c.105+1G>A		splice_donor intron	N/A	NP_001339534.1
	PCCA	NM_001127692.3		c.105+1G>A		splice_donor intron	N/A	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.105+1G>A		splice_donor intron	N/A	ENSP00000365462.1	P05165-1
	PCCA	ENST00000881637.1		c.105+1G>A		splice_donor intron	N/A	ENSP00000551696.1
	PCCA	ENST00000881640.1		c.105+1G>A		splice_donor intron	N/A	ENSP00000551699.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000836 AC: 1 AN: 119672 AF XY: 0.0000154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000471

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: 0.00000221 AC: 3 AN: 1357966 Hom.: 0 Cov.: 31 AF XY: 0.00000150 AC XY: 1 AN XY: 667516

African (AFR) AF: 0.0000353 AC: 1 AN: 28308

American (AMR) AF: 0.00 AC: 0 AN: 33118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24122

East Asian (EAS) AF: 0.00 AC: 0 AN: 32372

South Asian (SAS) AF: 0.00 AC: 0 AN: 73614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3974

European-Non Finnish (NFE) AF: 9.42e-7 AC: 1 AN: 1062004

Other (OTH) AF: 0.0000178 AC: 1 AN: 56288

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Propionic acidemia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Benign	0.69	D
PhyloP100		3.4
GERP RS		4.5
PromoterAI		-0.63	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: 23
DS_DL_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs879253804; hg19: chr13-100741480;