rs35719359

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000282.4(PCCA):c.1423A>G(p.Ile475Val) variant causes a missense change. The variant allele was found at a frequency of 0.047 in 1,609,050 control chromosomes in the GnomAD database, including 2,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 192 hom., cov: 32)

Exomes 𝑓: 0.048 ( 1967 hom. )

Consequence

PCCA
NM_000282.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 5.09

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015204549).

BP6

Variant 13-100309902-A-G is Benign according to our data. Variant chr13-100309902-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 92761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100309902-A-G is described in Lovd as [Likely_benign]. Variant chr13-100309902-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCA	NM_000282.4 link	c.1423A>G	p.Ile475Val	missense_variant	Exon 16 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.1423A>G	p.Ile475Val	missense_variant	Exon 16 of 24	1	NM_000282.4	ENSP00000365462.1		P05165-1

Frequencies

GnomAD3 genomes

AF:

0.0396

AC:

6025

AN:

152118

Hom.:

192

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0101

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.0234

Gnomad ASJ

AF:

0.0332

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.106

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0561

Gnomad OTH

AF:

0.0349

GnomAD3 exomes

AF:

0.0422

AC:

10605

AN:

251340

Hom.:

343

AF XY:

0.0428

AC XY:

5820

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00917

Gnomad AMR exome

AF:

0.0180

Gnomad ASJ exome

AF:

0.0373

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.0109

Gnomad FIN exome

AF:

0.103

Gnomad NFE exome

AF:

0.0581

Gnomad OTH exome

AF:

0.0471

GnomAD4 exome

AF:

0.0478

AC:

69625

AN:

1456814

Hom.:

1967

Cov.:

AF XY:

0.0468

AC XY:

33936

AN XY:

725130

show subpopulations

Gnomad4 AFR exome

AF:

0.00853

Gnomad4 AMR exome

AF:

0.0193

Gnomad4 ASJ exome

AF:

0.0382

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0111

Gnomad4 FIN exome

AF:

0.0979

Gnomad4 NFE exome

AF:

0.0530

Gnomad4 OTH exome

AF:

0.0423

GnomAD4 genome

AF:

0.0396

AC:

6023

AN:

152236

Hom.:

192

Cov.:

AF XY:

0.0412

AC XY:

3068

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0101

Gnomad4 AMR

AF:

0.0233

Gnomad4 ASJ

AF:

0.0332

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0116

Gnomad4 FIN

AF:

0.106

Gnomad4 NFE

AF:

0.0561

Gnomad4 OTH

AF:

0.0346

Alfa

AF:

0.0496

Hom.:

368

Bravo

AF:

0.0329

TwinsUK

AF:

0.0604

AC:

224

ALSPAC

AF:

0.0475

AC:

183

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.0506

AC:

435

ExAC

AF:

0.0425

AC:

5159

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0503

EpiControl

AF:

0.0491

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Propionic acidemia

Benign:6

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Oct 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:4

Mar 29, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PCCA c.1423A>G (p.Ile475Val) results in a conservative amino acid change located in the Biotin carboxylase, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.043 in 277082 control chromosomes in the gnomAD database and literature, including 391 homozygotes. The observed variant frequency is approximately 12.53 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCCA causing Propionic Acidemia phenotype (0.0034), strongly suggesting that the variant is benign. This variant has been reported in the literature in homozygous individuals affected with Propionic Acidemia but was also found in controls in the same study (Richard_1999). This report does not provide unequivocal conclusions about an association of the variant with Propionic Acidemia. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign (x2) and likely benign (x1). Based on the evidence outlined above, the variant was classified as benign. -

Sep 14, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

.;.;D

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.98

.;L;L

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.86

N;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.33

T;T;T

Sift4G

Benign

0.36

T;T;T

Polyphen

0.66

P;.;P

Vest4

0.21

MPC

0.22

ClinPred

0.017

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

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

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