rs16957276

Positions:

• chr13-100309915-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000282.4(PCCA):​c.1429+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,602,596 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (17 hom., cov: 32)
  • Exomes 𝑓: 0.017 (255 hom.)
• Consequence: PCCA NM_000282.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005723
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.173

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 13-100309915-A-G is Benign according to our data. Variant chr13-100309915-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 194593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100309915-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0136 (2077/152262) while in subpopulation SAS AF= 0.0207 (100/4826). AF 95% confidence interval is 0.0185. There are 17 homozygotes in gnomad4. There are 1014 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCCA	NM_000282.4	c.1429+7A>G		splice_region_variant, intron_variant		ENST00000376285.6	NP_000273.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCCA	ENST00000376285.6	c.1429+7A>G		splice_region_variant, intron_variant		1	NM_000282.4	ENSP00000365462.1

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2078 AN: 152144 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00988

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.0285

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0194

Gnomad OTH AF: 0.00862

GnomAD3 exomes AF: 0.0158 AC: 3970 AN: 251284 Hom.: 46 AF XY: 0.0169 AC XY: 2293 AN XY: 135822

Gnomad AFR exome AF: 0.00394

Gnomad AMR exome AF: 0.00761

Gnomad ASJ exome AF: 0.00884

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0214

Gnomad FIN exome AF: 0.0284

Gnomad NFE exome AF: 0.0191

Gnomad OTH exome AF: 0.0183

GnomAD4 exome AF: 0.0172 AC: 24944 AN: 1450334 Hom.: 255 Cov.: 27 AF XY: 0.0174 AC XY: 12560 AN XY: 722370

Gnomad4 AFR exome AF: 0.00337

Gnomad4 AMR exome AF: 0.00769

Gnomad4 ASJ exome AF: 0.0102

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.0226

Gnomad4 FIN exome AF: 0.0278

Gnomad4 NFE exome AF: 0.0180

Gnomad4 OTH exome AF: 0.0143

GnomAD4 genome AF: 0.0136 AC: 2077 AN: 152262 Hom.: 17 Cov.: 32 AF XY: 0.0136 AC XY: 1014 AN XY: 74442

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.00987

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0207

Gnomad4 FIN AF: 0.0285

Gnomad4 NFE AF: 0.0194

Gnomad4 OTH AF: 0.00853

Alfa AF: 0.0170 Hom.: 12

Bravo AF: 0.0115

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0162

EpiControl AF: 0.0184

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 05, 2018	Variant summary: The PCCA c.1429+7A>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 4420/277054 control chromosomes (51 homozygotes) at a frequency of 0.0159536, which is approximately 5 times the estimated maximal expected allele frequency of a pathogenic PCCA variant (0.003446), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Propionic acidemia Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 26, 2021	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.40
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs16957276; hg19: chr13-100962169;