NM_000282.4:c.184-17_184-16delGT

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000282.4(PCCA):c.184-17_184-16delGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,563,578 control chromosomes in the GnomAD database, including 9,092 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1214 hom., cov: 30)

Exomes 𝑓: 0.10 ( 7878 hom. )

Consequence

PCCA
NM_000282.4 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.885

Publications

2 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 -16 ACMG points.

BP6

Variant 13-100111820-ATG-A is Benign according to our data. Variant chr13-100111820-ATG-A is described in ClinVar as Benign. ClinVar VariationId is 196244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCA	NM_000282.4 link	c.184-17_184-16delGT		intron_variant	Intron 2 of 23	ENST00000376285.6	NP_000273.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCA	ENST00000376285.6 link	c.184-20_184-19delTG		intron_variant	Intron 2 of 23	1	NM_000282.4	ENSP00000365462.1

Frequencies

GnomAD3 genomes

AF:

0.118

AC:

17897

AN:

151908

Hom.:

1212

Cov.:

show subpopulations

Gnomad AFR

AF:

0.179

Gnomad AMI

AF:

0.0789

Gnomad AMR

AF:

0.104

Gnomad ASJ

AF:

0.128

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.0589

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.132

GnomAD2 exomes

AF:

0.0929

AC:

22682

AN:

244140

AF XY:

0.0949

show subpopulations

Gnomad AFR exome

AF:

0.173

Gnomad AMR exome

AF:

0.0699

Gnomad ASJ exome

AF:

0.139

Gnomad EAS exome

AF:

0.000443

Gnomad FIN exome

AF:

0.0564

Gnomad NFE exome

AF:

0.100

Gnomad OTH exome

AF:

0.112

GnomAD4 exome

AF:

0.0995

AC:

140483

AN:

1411550

Hom.:

7878

AF XY:

0.0997

AC XY:

70282

AN XY:

704592

show subpopulations

African (AFR)

AF:

0.183

AC:

5937

AN:

32394

American (AMR)

AF:

0.0734

AC:

3244

AN:

44216

Ashkenazi Jewish (ASJ)

AF:

0.140

AC:

3618

AN:

25756

East Asian (EAS)

AF:

0.000534

AC:

AN:

39322

South Asian (SAS)

AF:

0.113

AC:

9519

AN:

84566

European-Finnish (FIN)

AF:

0.0579

AC:

3079

AN:

53170

Middle Eastern (MID)

AF:

0.159

AC:

738

AN:

4646

European-Non Finnish (NFE)

AF:

0.101

AC:

107988

AN:

1068930

Other (OTH)

AF:

0.108

AC:

6339

AN:

58550

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

5643

11287

16930

22574

28217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3930

7860

11790

15720

19650

<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:

0.118

AC:

17933

AN:

152028

Hom.:

1214

Cov.:

AF XY:

0.115

AC XY:

8560

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.180

AC:

7446

AN:

41434

American (AMR)

AF:

0.104

AC:

1593

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

445

AN:

3464

East Asian (EAS)

AF:

0.00116

AC:

AN:

5174

South Asian (SAS)

AF:

0.105

AC:

505

AN:

4820

European-Finnish (FIN)

AF:

0.0589

AC:

622

AN:

10564

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.102

AC:

6916

AN:

67970

Other (OTH)

AF:

0.131

AC:

275

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

761

1523

2284

3046

3807

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

186

372

558

744

930

<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:

0.114

Hom.:

194

Bravo

AF:

0.123

Asia WGS

AF:

0.0570

AC:

196

AN:

3464

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 17, 2019

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.184-17_184-16delGT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.093 in 244140 control chromosomes in the gnomAD database, including 1230 homozygotes. The observed variant frequency is approximately 27-folds over 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. Two ClinVar submissions (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Dec 02, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 23, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 2014

GeneDx

Significance:Benign

Review Status:flagged submission

Collection Method:clinical testing

The variant is found in UCD-MET panel(s). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 10, 2016

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. -

Propionic acidemia

Benign:4

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: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

- -

Jan 01, 2011

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.89

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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