13-100368479-G-T

Position:

chr13-100368479-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000376285.6(PCCA):c.1651G>T(p.Val551Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00865 in 1,565,676 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. V551I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0070 ( 4 hom., cov: 31)

Exomes 𝑓: 0.0088 ( 70 hom. )

Consequence

PCCA
ENST00000376285.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7O:1

Conservation

PhyloP100: -0.163

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050973594).

BP6

Variant 13-100368479-G-T is Benign according to our data. Variant chr13-100368479-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38865.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=4, not_provided=1}. Variant chr13-100368479-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00883 (12482/1413920) while in subpopulation MID AF= 0.0362 (205/5656). AF 95% confidence interval is 0.0322. There are 70 homozygotes in gnomad4_exome. There are 6331 alleles in male gnomad4_exome subpopulation. Median coverage is 27. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCCA	NM_000282.4 linkuse as main transcript	c.1651G>T	p.Val551Phe	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.1651G>T	p.Val551Phe	missense_variant	19/24	1	NM_000282.4	ENSP00000365462	P1	P05165-1

Frequencies

GnomAD3 genomes

AF:

0.00698

AC:

1059

AN:

151638

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00191

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0128

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00519

Gnomad FIN

AF:

0.00229

Gnomad MID

AF:

0.0446

Gnomad NFE

AF:

0.00959

Gnomad OTH

AF:

0.0159

GnomAD3 exomes

AF:

0.00799

AC:

2006

AN:

250938

Hom.:

AF XY:

0.00856

AC XY:

1161

AN XY:

135624

show subpopulations

Gnomad AFR exome

AF:

0.00179

Gnomad AMR exome

AF:

0.00826

Gnomad ASJ exome

AF:

0.00924

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00662

Gnomad FIN exome

AF:

0.00222

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.00883

AC:

12482

AN:

1413920

Hom.:

Cov.:

AF XY:

0.00896

AC XY:

6331

AN XY:

706318

show subpopulations

Gnomad4 AFR exome

AF:

0.00198

Gnomad4 AMR exome

AF:

0.00805

Gnomad4 ASJ exome

AF:

0.0100

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00682

Gnomad4 FIN exome

AF:

0.00272

Gnomad4 NFE exome

AF:

0.00963

Gnomad4 OTH exome

AF:

0.00977

GnomAD4 genome

AF:

0.00697

AC:

1058

AN:

151756

Hom.:

Cov.:

AF XY:

0.00739

AC XY:

548

AN XY:

74150

show subpopulations

Gnomad4 AFR

AF:

0.00191

Gnomad4 AMR

AF:

0.0128

Gnomad4 ASJ

AF:

0.0110

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00540

Gnomad4 FIN

AF:

0.00229

Gnomad4 NFE

AF:

0.00959

Gnomad4 OTH

AF:

0.0157

Alfa

AF:

0.00908

Hom.:

Bravo

AF:

0.00745

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00802

AC:

ExAC

AF:

0.00769

AC:

934

EpiCase

AF:

0.0144

EpiControl

AF:

0.0144

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Propionic acidemia

Uncertain:1Benign:4Other:1

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 18, 2022	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2022

PCCA: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

5.4

DANN

Benign

0.59

DEOGEN2

Benign

0.41

.;.;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.69

T;T;T;T

MetaRNN

Benign

0.0051

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.2

.;L;L;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Uncertain

0.49

Sift

Benign

0.51

T;T;T;D

Sift4G

Benign

0.71

T;T;T;D

Polyphen

0.072

B;.;B;.

Vest4

0.25

MVP

0.24

MPC

0.19

ClinPred

0.0026

GERP RS

-1.8

Varity_R

0.10

gMVP

0.54

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