rs118169528

Positions:

chr13-100368504-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000282.4(PCCA):c.1676G>T(p.Trp559Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000892 in 1,608,618 control chromosomes in the GnomAD database, including 23 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 0.0012 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00086 ( 22 hom. )

Consequence

PCCA
NM_000282.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:4

Conservation

PhyloP100: 6.49

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008779764).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00118 (178/151316) while in subpopulation EAS AF= 0.0318 (162/5092). AF 95% confidence interval is 0.0278. There are 1 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCCA	NM_000282.4 linkuse as main transcript	c.1676G>T	p.Trp559Leu	missense_variant	19/24	ENST00000376285.6	NP_000273.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCCA	ENST00000376285.6 linkuse as main transcript	c.1676G>T	p.Trp559Leu	missense_variant	19/24	1	NM_000282.4	ENSP00000365462	P1	P05165-1

Frequencies

GnomAD3 genomes

AF:

0.00117

AC:

177

AN:

151196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0318

Gnomad SAS

AF:

0.00167

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.00302

AC:

760

AN:

251274

Hom.:

AF XY:

0.00266

AC XY:

361

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0399

Gnomad SAS exome

AF:

0.000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000863

AC:

1257

AN:

1457302

Hom.:

Cov.:

AF XY:

0.000813

AC XY:

590

AN XY:

725268

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0282

Gnomad4 SAS exome

AF:

0.000721

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00108

GnomAD4 genome

AF:

0.00118

AC:

178

AN:

151316

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

113

AN XY:

73816

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0318

Gnomad4 SAS

AF:

0.00188

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.000476

Alfa

AF:

0.00149

Hom.:

Bravo

AF:

0.00193

ExAC

AF:

0.00308

AC:

374

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Propionic acidemia

Pathogenic:1Uncertain:4Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Pathogenic, flagged submission	research	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jan 01, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

PCCA: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

.;.;D;T

Eigen

Benign

0.017

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

D;D;D;D

MetaRNN

Benign

0.0088

T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.5

.;M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-6.6

D;D;D;D

REVEL

Uncertain

0.50

Sift

Benign

0.11

T;T;T;D

Sift4G

Uncertain

0.033

D;D;D;D

Polyphen

0.42

B;.;B;.

Vest4

0.81

MVP

0.88

MPC

0.25

ClinPred

0.13

GERP RS

4.8

Varity_R

0.61

gMVP

0.86

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

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