13-100515544-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

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. 15/22 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

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

propionic acidemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen, Orphanet

PCCA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 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 VariationId is 459937.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00261 (398/152294) while in subpopulation NFE AF = 0.00417 (284/68028). AF 95% confidence interval is 0.00378. There are 1 homozygotes in GnomAd4. There are 199 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCA	NM_000282.4 link	c.2017G>C	p.Val673Leu	missense_variant	Exon 22 of 24	ENST00000376285.6	NP_000273.2	P05165-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCA	ENST00000376285.6 link	c.2017G>C	p.Val673Leu	missense_variant	Exon 22 of 24	1	NM_000282.4	ENSP00000365462.1		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

GnomAD2 exomes

AF:

0.00247

AC:

621

AN:

251292

AF XY:

0.00254

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 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

African (AFR)

AF:

0.000299

AC:

AN:

33474

American (AMR)

AF:

0.000179

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00191

AC:

165

AN:

86250

European-Finnish (FIN)

AF:

0.00443

AC:

236

AN:

53286

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00374

AC:

4164

AN:

1111954

Other (OTH)

AF:

0.00222

AC:

134

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

258

516

773

1031

1289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

150

300

450

600

750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00261

AC:

398

AN:

152294

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

199

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41566

American (AMR)

AF:

0.000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00249

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00678

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00417

AC:

284

AN:

68028

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2021

Division of Genetic Medicine, Lausanne University Hospital

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PCCA: BP4 -

Jan 13, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PCCA-related disorder

Benign:1

Dec 05, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.42

.;T;T

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

MutationAssessor

Benign

0.57

.;N;.

PhyloP100

2.8

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

PromoterAI

-0.00060

Neutral

(source)

Varity_R

0.35

gMVP

0.48

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over