dbSNP rs35719359: PCCA:p.Ile475Val (chr13-100309902-A-G) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000282.4(PCCA):c.1423A>G(p.Ile475Val) variant causes a missense change. The variant allele was found at a frequency of 0.047 in 1,609,050 control chromosomes in the GnomAD database, including 2,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I475F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.040 ( 192 hom., cov: 32)

Exomes 𝑓: 0.048 ( 1967 hom. )

Consequence

PCCA
NM_000282.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 5.09

Publications

17 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: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P

PCCA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000282.4

BP4

Computational evidence support a benign effect (MetaRNN=0.015204549).

BP6

Variant 13-100309902-A-G is Benign according to our data. Variant chr13-100309902-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0547 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	UniProt
PCCA	NM_000282.4	MANE Select	c.1423A>G	p.Ile475Val	missense	Exon 16 of 24	NP_000273.2	P05165-1
PCCA	NM_001352605.2		c.1423A>G	p.Ile475Val	missense	Exon 16 of 23	NP_001339534.1
PCCA	NM_001127692.3		c.1345A>G	p.Ile449Val	missense	Exon 15 of 23	NP_001121164.1	P05165-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCCA	ENST00000376285.6	TSL:1 MANE Select	c.1423A>G	p.Ile475Val	missense	Exon 16 of 24	ENSP00000365462.1	P05165-1
PCCA	ENST00000881637.1		c.1546A>G	p.Ile516Val	missense	Exon 17 of 25	ENSP00000551696.1
PCCA	ENST00000881640.1		c.1528A>G	p.Ile510Val	missense	Exon 17 of 25	ENSP00000551699.1

Frequencies

GnomAD3 genomes

AF:

0.0396

AC:

6025

AN:

152118

Hom.:

192

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0101

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.0234

Gnomad ASJ

AF:

0.0332

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.106

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0561

Gnomad OTH

AF:

0.0349

GnomAD2 exomes

AF:

0.0422

AC:

10605

AN:

251340

AF XY:

0.0428

show subpopulations

Gnomad AFR exome

AF:

0.00917

Gnomad AMR exome

AF:

0.0180

Gnomad ASJ exome

AF:

0.0373

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.103

Gnomad NFE exome

AF:

0.0581

Gnomad OTH exome

AF:

0.0471

GnomAD4 exome

AF:

0.0478

AC:

69625

AN:

1456814

Hom.:

1967

Cov.:

AF XY:

0.0468

AC XY:

33936

AN XY:

725130

show subpopulations

African (AFR)

AF:

0.00853

AC:

285

AN:

33416

American (AMR)

AF:

0.0193

AC:

865

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0382

AC:

996

AN:

26096

East Asian (EAS)

AF:

0.000202

AC:

AN:

39624

South Asian (SAS)

AF:

0.0111

AC:

955

AN:

86176

European-Finnish (FIN)

AF:

0.0979

AC:

5226

AN:

53372

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0530

AC:

58653

AN:

1107420

Other (OTH)

AF:

0.0423

AC:

2547

AN:

60244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

2803

5607

8410

11214

14017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2060

4120

6180

8240

10300

<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:

0.0396

AC:

6023

AN:

152236

Hom.:

192

Cov.:

AF XY:

0.0412

AC XY:

3068

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0101

AC:

419

AN:

41560

American (AMR)

AF:

0.0233

AC:

356

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0332

AC:

115

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.0116

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.106

AC:

1127

AN:

10598

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0561

AC:

3818

AN:

68008

Other (OTH)

AF:

0.0346

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

298

597

895

1194

1492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0473

Hom.:

519

Bravo

AF:

0.0329

TwinsUK

AF:

0.0604

AC:

224

ALSPAC

AF:

0.0475

AC:

183

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.0506

AC:

435

ExAC

AF:

0.0425

AC:

5159

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0503

EpiControl

AF:

0.0491

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Propionic acidemia (6)

not specified (4)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.98

PhyloP100

5.1

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.86

REVEL

Uncertain

0.40

Sift

Benign

0.33

Sift4G

Benign

0.36

Polyphen

0.66

Vest4

0.21

MPC

0.22

ClinPred

0.017

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.70

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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