13-100111820-ATG-A

Variant names:

• chr13-100111820-ATG-A
• rs111778723
• NM_000282.4:c.184-17_184-16delGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.885

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]

ACMG classification

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 id is 196244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100111820-ATG-A is described in Lovd as [Benign].
• 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	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	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.: 30

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

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

Gnomad4 AFR exome AF: 0.183 AC: 5937 AN: 32394

Gnomad4 AMR exome AF: 0.0734 AC: 3244 AN: 44216

Gnomad4 ASJ exome AF: 0.140 AC: 3618 AN: 25756

Gnomad4 EAS exome AF: 0.000534 AC: 21 AN: 39322

Gnomad4 SAS exome AF: 0.113 AC: 9519 AN: 84566

Gnomad4 FIN exome AF: 0.0579 AC: 3079 AN: 53170

Gnomad4 NFE exome AF: 0.101 AC: 107988 AN: 1068930

Gnomad4 Remaining exome AF: 0.108 AC: 6339 AN: 58550

GnomAD4 genome AF: 0.118 AC: 17933 AN: 152028 Hom.: 1214 Cov.: 30 AF XY: 0.115 AC XY: 8560 AN XY: 74326

Gnomad4 AFR AF: 0.180 AC: 0.179707 AN: 0.179707

Gnomad4 AMR AF: 0.104 AC: 0.104186 AN: 0.104186

Gnomad4 ASJ AF: 0.128 AC: 0.128464 AN: 0.128464

Gnomad4 EAS AF: 0.00116 AC: 0.00115964 AN: 0.00115964

Gnomad4 SAS AF: 0.105 AC: 0.104772 AN: 0.104772

Gnomad4 FIN AF: 0.0589 AC: 0.0588792 AN: 0.0588792

Gnomad4 NFE AF: 0.102 AC: 0.101751 AN: 0.101751

Gnomad4 OTH AF: 0.131 AC: 0.130579 AN: 0.130579

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

Submissions by phenotype

not specified Benign:8

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

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

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

- -

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. -

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=100/0	polymorphism (auto)

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

LitVar

Other links and lift over

dbSNP: rs111778723; hg19: chr13-100764074; COSMIC: COSV66189957;