13-100273210-C-G

Position:

• chr13-100273210-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_000282.4(PCCA):​c.929C>G​(p.Ala310Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000656 in 1,612,482 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (2 hom.)
• Consequence: PCCA NM_000282.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 4.92

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 -7 ACMG points.

• PM1: In a domain ATP-grasp (size 197) in uniprot entity PCCA_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000282.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.014012933).
• BP6: Variant 13-100273210-C-G is Benign according to our data. Variant chr13-100273210-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 788170.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}. Variant chr13-100273210-C-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCCA	NM_000282.4	c.929C>G	p.Ala310Gly	missense_variant	12/24	ENST00000376285.6	NP_000273.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCCA	ENST00000376285.6	c.929C>G	p.Ala310Gly	missense_variant	12/24	1	NM_000282.4	ENSP00000365462.1

Frequencies

GnomAD3 genomes AF: 0.000612 AC: 93 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000705 AC: 177 AN: 251176 Hom.: 1 AF XY: 0.000773 AC XY: 105 AN XY: 135748

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00705

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000766

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000660 AC: 964 AN: 1460326 Hom.: 2 Cov.: 29 AF XY: 0.000692 AC XY: 503 AN XY: 726574

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00597

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.000656

Gnomad4 OTH exome AF: 0.000779

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74380

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000994 Hom.: 1

Bravo AF: 0.000578

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000692 AC: 84

EpiCase AF: 0.00104

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Propionic acidemia Uncertain:2 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
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 provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with seizures who was also compound heterozygous for a second variant in PCCA, however, detailed clinical and biochemical results were not provided (PMID: 31780880); This variant is associated with the following publications: (PMID: 34426522, 34440436, 31780880) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	.;.;D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.1	.;L;L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.069	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.043	B;.;B
Vest4		0.31
MVP		0.92
MPC		0.18
ClinPred		0.036	T
GERP RS		3.8
Varity_R		0.072
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs146927771; hg19: chr13-100925464;