NM_000282.4:c.1896A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_000282.4(PCCA):c.1896A>G(p.Thr632Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,514,888 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T632T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

PCCA
NM_000282.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.445

Publications

0 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.048).

BP6

Variant 13-100449302-A-G is Benign according to our data. Variant chr13-100449302-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 459936.

BP7

Synonymous conserved (PhyloP=0.445 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00116 (1582/1362602) while in subpopulation NFE AF = 0.00141 (1479/1046040). AF 95% confidence interval is 0.00135. There are 2 homozygotes in GnomAdExome4. There are 747 alleles in the male GnomAdExome4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCA	NM_000282.4 link	c.1896A>G	p.Thr632Thr	synonymous_variant	Exon 21 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.1896A>G	p.Thr632Thr	synonymous_variant	Exon 21 of 24	1	NM_000282.4	ENSP00000365462.1		P05165-1

Frequencies

GnomAD3 genomes

AF:

0.000690

AC:

105

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00123

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000602

AC:

AN:

152710

AF XY:

0.000621

show subpopulations

Gnomad AFR exome

AF:

0.000344

Gnomad AMR exome

AF:

0.0000411

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000718

Gnomad NFE exome

AF:

0.00126

Gnomad OTH exome

AF:

0.000919

GnomAD4 exome

AF:

0.00116

AC:

1582

AN:

1362602

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

747

AN XY:

674242

show subpopulations

African (AFR)

AF:

0.000227

AC:

AN:

30888

American (AMR)

AF:

0.0000282

AC:

AN:

35510

Ashkenazi Jewish (ASJ)

AF:

0.0000401

AC:

AN:

24916

East Asian (EAS)

AF:

0.00

AC:

AN:

35530

South Asian (SAS)

AF:

0.00

AC:

AN:

78120

European-Finnish (FIN)

AF:

0.00124

AC:

AN:

49218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.00141

AC:

1479

AN:

1046040

Other (OTH)

AF:

0.000581

AC:

AN:

56754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

125

187

250

312

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.000689

AC:

105

AN:

152286

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41574

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00123

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000747

Hom.:

Bravo

AF:

0.000559

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Propionic acidemia

Uncertain:2Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jan 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 17, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PCCA: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

6.4

(source)

DANN

Benign

0.78

PhyloP100

0.45

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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