NM_000282.4:c.231+1G>C

Variant names:

• chr13-100111889-G-C
• rs972937270
• NM_000282.4:c.231+1G>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Moderate PS3 PM2 PP5_Very_Strong

The NM_000282.4(PCCA):​c.231+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000497 in 1,610,276 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000917965: The variant allele was found at a frequency of 1.4e-05 in 276520 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PCCA causing Propionic Acidemia (1.4e-05 vs 0.0034), allowing no conclusion about variant significance. The c.231+1G>C variant has been reported in the literature in individuals affected with Propionic Acidemia (Desviat_2006, Desviat_2009). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Desviat_2009 Desviat_2009; SCV002060237: Functional assessments of this variant are available in the literature (PMID:19157943).".

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PCCA NM_000282.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.26
• 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 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.021947874 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000917965: The variant allele was found at a frequency of 1.4e-05 in 276520 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PCCA causing Propionic Acidemia (1.4e-05 vs 0.0034), allowing no conclusion about variant significance. The c.231+1G>C variant has been reported in the literature in individuals affected with Propionic Acidemia (Desviat_2006, Desviat_2009). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Desviat_2009 Desviat_2009; SCV002060237: Functional assessments of this variant are available in the literature (PMID: 19157943).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-100111889-G-C is Pathogenic according to our data. Variant chr13-100111889-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 550113.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.231+1G>C		splice_donor intron	N/A	NP_000273.2	P05165-1
	PCCA	NM_001352605.2		c.231+1G>C		splice_donor intron	N/A	NP_001339534.1
	PCCA	NM_001127692.3		c.153+1G>C		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.231+1G>C		splice_donor intron	N/A	ENSP00000365462.1	P05165-1
	PCCA	ENST00000881637.1		c.231+1G>C		splice_donor intron	N/A	ENSP00000551696.1
	PCCA	ENST00000881640.1		c.231+1G>C		splice_donor intron	N/A	ENSP00000551699.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250554 AF XY: 0.00000738

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458228 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 725660

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.00 AC: 0 AN: 86104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5526

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109264

Other (OTH) AF: 0.00 AC: 0 AN: 60228

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152048 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74282

African (AFR) AF: 0.0000483 AC: 2 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Propionic acidemia (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		6.3
GERP RS		5.8
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_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: rs972937270; hg19: chr13-100764143;