13-100368479-G-T

Variant names:

• chr13-100368479-G-T
• rs61749895
• NM_000282.4:c.1651G>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000282.4(PCCA):​c.1651G>T​(p.Val551Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00865 in 1,565,676 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V551I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0070 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0088 (70 hom.)
• Consequence: PCCA NM_000282.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7 O:1
• Conservation: PhyloP100: -0.163
• Publications: 16 publications found

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050973594).
• BP6: Variant 13-100368479-G-T is Benign according to our data. Variant chr13-100368479-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 38865.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00697 (1058/151756) while in subpopulation AMR AF = 0.0128 (194/15184). AF 95% confidence interval is 0.0113. There are 4 homozygotes in GnomAd4. There are 548 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCA	NM_000282.4	MANE Select	c.1651G>T	p.Val551Phe	missense	Exon 19 of 24	NP_000273.2
	PCCA	NM_001352605.2		c.1651G>T	p.Val551Phe	missense	Exon 19 of 23	NP_001339534.1
	PCCA	NM_001127692.3		c.1573G>T	p.Val525Phe	missense	Exon 18 of 23	NP_001121164.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCA	ENST00000376285.6	TSL:1 MANE Select	c.1651G>T	p.Val551Phe	missense	Exon 19 of 24	ENSP00000365462.1
	PCCA	ENST00000376286.8	TSL:2	c.1573G>T	p.Val525Phe	missense	Exon 18 of 23	ENSP00000365463.4
	PCCA	ENST00000376279.7	TSL:2	c.1651G>T	p.Val551Phe	missense	Exon 19 of 23	ENSP00000365456.3

Frequencies

GnomAD3 genomes AF: 0.00698 AC: 1059 AN: 151638 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00519

Gnomad FIN AF: 0.00229

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.00959

Gnomad OTH AF: 0.0159

GnomAD2 exomes AF: 0.00799 AC: 2006 AN: 250938 AF XY: 0.00856

Gnomad AFR exome AF: 0.00179

Gnomad AMR exome AF: 0.00826

Gnomad ASJ exome AF: 0.00924

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00883 AC: 12482 AN: 1413920 Hom.: 70 Cov.: 27 AF XY: 0.00896 AC XY: 6331 AN XY: 706318

African (AFR) AF: 0.00198 AC: 64 AN: 32402

American (AMR) AF: 0.00805 AC: 359 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.0100 AC: 259 AN: 25834

East Asian (EAS) AF: 0.00 AC: 0 AN: 39308

South Asian (SAS) AF: 0.00682 AC: 579 AN: 84840

European-Finnish (FIN) AF: 0.00272 AC: 145 AN: 53366

Middle Eastern (MID) AF: 0.0362 AC: 205 AN: 5656

European-Non Finnish (NFE) AF: 0.00963 AC: 10298 AN: 1069270

Other (OTH) AF: 0.00977 AC: 573 AN: 58658

GnomAD4 genome AF: 0.00697 AC: 1058 AN: 151756 Hom.: 4 Cov.: 31 AF XY: 0.00739 AC XY: 548 AN XY: 74150

African (AFR) AF: 0.00191 AC: 79 AN: 41380

American (AMR) AF: 0.0128 AC: 194 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00540 AC: 26 AN: 4814

European-Finnish (FIN) AF: 0.00229 AC: 24 AN: 10482

Middle Eastern (MID) AF: 0.0411 AC: 12 AN: 292

European-Non Finnish (NFE) AF: 0.00959 AC: 652 AN: 67984

Other (OTH) AF: 0.0157 AC: 33 AN: 2102

Alfa AF: 0.00869 Hom.: 14

Bravo AF: 0.00745

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.00769 AC: 934

EpiCase AF: 0.0144

EpiControl AF: 0.0144

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Propionic acidemia Uncertain:1 Benign:4 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 07, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PCCA: BP4, BS2

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	5.4
DANN	Benign	0.59
DEOGEN2	Benign	0.41	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.16
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.49
Sift	Benign	0.51	T
Sift4G	Benign	0.71	T
Polyphen		0.072	B
Vest4		0.25
MVP		0.24
MPC		0.19
ClinPred		0.0026	T
GERP RS		-1.8
PromoterAI		0.0057	Neutral
Varity_R		0.10
gMVP		0.54
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs61749895; hg19: chr13-101020733;