13-100515544-G-C

Position:

chr13-100515544-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_000282.4(PCCA):c.2017G>C(p.Val673Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,613,964 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V673I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0026 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0032 ( 8 hom. )

Consequence

PCCA
NM_000282.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.82

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000282.4

BP4

Computational evidence support a benign effect (MetaRNN=0.010170162).

BP6

Variant 13-100515544-G-C is Benign according to our data. Variant chr13-100515544-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 459937.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr13-100515544-G-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCCA	NM_000282.4 linkuse as main transcript	c.2017G>C	p.Val673Leu	missense_variant	22/24	ENST00000376285.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCCA	ENST00000376285.6 linkuse as main transcript	c.2017G>C	p.Val673Leu	missense_variant	22/24	1	NM_000282.4	P1	P05165-1

Frequencies

GnomAD3 genomes

AF:

0.00262

AC:

398

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00678

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00417

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.00247

AC:

621

AN:

251292

Hom.:

AF XY:

0.00254

AC XY:

345

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00167

Gnomad FIN exome

AF:

0.00502

Gnomad NFE exome

AF:

0.00388

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.00323

AC:

4720

AN:

1461670

Hom.:

Cov.:

AF XY:

0.00321

AC XY:

2331

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00191

Gnomad4 FIN exome

AF:

0.00443

Gnomad4 NFE exome

AF:

0.00374

Gnomad4 OTH exome

AF:

0.00222

GnomAD4 genome

AF:

0.00261

AC:

398

AN:

152294

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

199

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.00678

Gnomad4 NFE

AF:

0.00417

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00286

Hom.:

Bravo

AF:

0.00189

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00442

AC:

ExAC

AF:

0.00260

AC:

316

EpiCase

AF:

0.00354

EpiControl

AF:

0.00267

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Propionic acidemia

Uncertain:1Benign:2

Benign, no assertion criteria provided	clinical testing	Division of Genetic Medicine, Lausanne University Hospital	Jan 13, 2021	The p.Val673Leu in PCCA has been found in homozygous state in three individuals without a phenotype of propionicacidemia. It has been previously identified as VUS but was never found in previous publications. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	PCCA: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2021	- -

PCCA-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.93

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.97

D;D;D

M_CAP

Benign

0.044

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-0.67

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.4

N;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.39

T;T;T

Sift4G

Benign

0.41

T;T;D

Polyphen

0.0020

B;B;.

Vest4

0.60

MVP

0.72

MPC

0.15

ClinPred

0.010

GERP RS

2.8

Varity_R

0.35

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over