13-100089101-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000282.4(PCCA):c.-20G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00042 in 1,470,070 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (4 hom.)
• Consequence: PCCA NM_000282.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.335

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 13-100089101-G-A is Benign according to our data. Variant chr13-100089101-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 310840.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCCA	NM_000282.4	c.-20G>A		5_prime_UTR_variant	1/24	ENST00000376285.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCCA	ENST00000376285.6	c.-20G>A		5_prime_UTR_variant	1/24	1	NM_000282.4	P1
PCCA	ENST00000376279.7	c.-20G>A		5_prime_UTR_variant	1/23	2
PCCA	ENST00000376286.8	c.-20G>A		5_prime_UTR_variant	1/23	2
PCCA	ENST00000647303.1	c.-20G>A		5_prime_UTR_variant, NMD_transcript_variant	1/21

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000687 AC: 76 AN: 110652 Hom.: 0 AF XY: 0.000802 AC XY: 48 AN XY: 59844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00361

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000234

Gnomad OTH exome AF: 0.000350

GnomAD4 exome AF: 0.000430 AC: 567 AN: 1317734 Hom.: 4 Cov.: 30 AF XY: 0.000494 AC XY: 318 AN XY: 643508

Gnomad4 AFR exome AF: 0.0000732

Gnomad4 AMR exome AF: 0.000459

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000327

Gnomad4 SAS exome AF: 0.00341

Gnomad4 FIN exome AF: 0.0000446

Gnomad4 NFE exome AF: 0.000263

Gnomad4 OTH exome AF: 0.000608

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74488

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000429 Hom.: 0

Bravo AF: 0.000246

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Propionic acidemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	8.1
Dann	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs374941593; hg19: chr13-100741355;