chr13-100368573-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 18/23 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

Splicing: ADA: 0.0004345

Clinical Significance

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

Conservation

PhyloP100: 0.397

Publications

10 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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000282.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCCA	NM_000282.4	MANE Select	c.1745C>T	p.Ser582Leu	missense splice_region	Exon 19 of 24	NP_000273.2
PCCA	NM_001352605.2		c.1745C>T	p.Ser582Leu	missense splice_region	Exon 19 of 23	NP_001339534.1
PCCA	NM_001127692.3		c.1667C>T	p.Ser556Leu	missense splice_region	Exon 18 of 23	NP_001121164.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCCA	ENST00000376285.6	TSL:1 MANE Select	c.1745C>T	p.Ser582Leu	missense splice_region	Exon 19 of 24	ENSP00000365462.1
PCCA	ENST00000881637.1		c.1868C>T	p.Ser623Leu	missense splice_region	Exon 20 of 25	ENSP00000551696.1
PCCA	ENST00000881640.1		c.1850C>T	p.Ser617Leu	missense splice_region	Exon 20 of 25	ENSP00000551699.1

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2269

AN:

151692

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00419

AC:

1053

AN:

251170

AF XY:

0.00326

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 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.:

Cov.:

AF XY:

0.00135

AC XY:

957

AN XY:

709966

show subpopulations

African (AFR)

AF:

0.0529

AC:

1717

AN:

32476

American (AMR)

AF:

0.00331

AC:

148

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.0000386

AC:

AN:

25902

East Asian (EAS)

AF:

0.00

AC:

AN:

39332

South Asian (SAS)

AF:

0.000152

AC:

AN:

85426

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00282

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.0000995

AC:

107

AN:

1075720

Other (OTH)

AF:

0.00364

AC:

215

AN:

58986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

172

259

345

431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.0150

AC:

2280

AN:

151810

Hom.:

Cov.:

AF XY:

0.0148

AC XY:

1099

AN XY:

74176

show subpopulations

African (AFR)

AF:

0.0517

AC:

2141

AN:

41398

American (AMR)

AF:

0.00655

AC:

100

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000419

AC:

AN:

4774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000177

AC:

AN:

67918

Other (OTH)

AF:

0.0119

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

106

213

319

426

532

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00573

Hom.:

Bravo

AF:

0.0174

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0508

AC:

224

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00493

AC:

599

Asia WGS

AF:

0.00289

AC:

AN:

3476

EpiCase

AF:

0.000436

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Propionic acidemia (4)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Uncertain

0.42

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

0.40

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.96

REVEL

Benign

0.23

Sift

Benign

0.35

Sift4G

Benign

0.42

Polyphen

0.0010

Vest4

0.15

MVP

0.44

MPC

0.12

ClinPred

0.0030

GERP RS

0.53

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.029

gMVP

0.57

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over