chr13-100368573-C-T

Variant summary

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

The NM_000282.4(PCCA):​c.1745C>T​(p.Ser582Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 1,573,368 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S582S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.015 ( 69 hom., cov: 31)
Exomes 𝑓: 0.0016 ( 50 hom. )

Consequence

PCCA
NM_000282.4 missense, splice_region

Scores

1
17
Splicing: ADA: 0.0004345
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.397
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0021552444).
BP6
Variant 13-100368573-C-T is Benign according to our data. Variant chr13-100368573-C-T is described in ClinVar as [Benign]. Clinvar id is 235448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0508 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PCCANM_000282.4 linkc.1745C>T p.Ser582Leu missense_variant, splice_region_variant Exon 19 of 24 ENST00000376285.6 NP_000273.2 P05165-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PCCAENST00000376285.6 linkc.1745C>T p.Ser582Leu missense_variant, splice_region_variant Exon 19 of 24 1 NM_000282.4 ENSP00000365462.1 P05165-1

Frequencies

GnomAD3 genomes
AF:
0.0150
AC:
2269
AN:
151692
Hom.:
68
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0516
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00656
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000419
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000177
Gnomad OTH
AF:
0.0120
GnomAD3 exomes
AF:
0.00419
AC:
1053
AN:
251170
Hom.:
25
AF XY:
0.00326
AC XY:
442
AN XY:
135764
show subpopulations
Gnomad AFR exome
AF:
0.0566
Gnomad AMR exome
AF:
0.00278
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000176
Gnomad OTH exome
AF:
0.00245
GnomAD4 exome
AF:
0.00156
AC:
2217
AN:
1421558
Hom.:
50
Cov.:
24
AF XY:
0.00135
AC XY:
957
AN XY:
709966
show subpopulations
Gnomad4 AFR exome
AF:
0.0529
Gnomad4 AMR exome
AF:
0.00331
Gnomad4 ASJ exome
AF:
0.0000386
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000152
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000995
Gnomad4 OTH exome
AF:
0.00364
GnomAD4 genome
AF:
0.0150
AC:
2280
AN:
151810
Hom.:
69
Cov.:
31
AF XY:
0.0148
AC XY:
1099
AN XY:
74176
show subpopulations
Gnomad4 AFR
AF:
0.0517
Gnomad4 AMR
AF:
0.00655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000419
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000177
Gnomad4 OTH
AF:
0.0119
Alfa
AF:
0.00260
Hom.:
20
Bravo
AF:
0.0174
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.0508
AC:
224
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.00493
AC:
599
Asia WGS
AF:
0.00289
AC:
10
AN:
3476
EpiCase
AF:
0.000436
EpiControl
AF:
0.000296

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Propionic acidemia Benign:4
Sep 08, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 13, 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. -

Sep 16, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:2
Jun 04, 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: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:2
Jan 11, 2016
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
15
DANN
Benign
0.66
DEOGEN2
Uncertain
0.42
.;.;T;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.16
N
LIST_S2
Benign
0.69
T;T;T;T
MetaRNN
Benign
0.0022
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.0
.;L;L;.
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-0.96
N;N;N;N
REVEL
Benign
0.23
Sift
Benign
0.35
T;T;T;T
Sift4G
Benign
0.42
T;T;T;T
Polyphen
0.0010
B;.;B;.
Vest4
0.15
MVP
0.44
MPC
0.12
ClinPred
0.0030
T
GERP RS
0.53
Varity_R
0.029
gMVP
0.57

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00043
dbscSNV1_RF
Benign
0.26
SpliceAI score (max)
0.080
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.

Other links and lift over

dbSNP: rs16957356; hg19: chr13-101020827; API