13-100530281-C-T

Variant names:

• chr13-100530281-C-T
• rs41281122
• NM_000282.4:c.*115C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000282.4(PCCA):​c.*115C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00935 in 850,454 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0097 (43 hom.)
• Consequence: PCCA NM_000282.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.444

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]

GGACT (HGNC:25100): (gamma-glutamylamine cyclotransferase) The protein encoded by this gene aids in the proteolytic degradation of crosslinked fibrin by breaking down isodipeptide L-gamma-glutamyl-L-epsilon-lysine, a byproduct of fibrin degradation. The reaction catalyzed by the encoded gamma-glutamylaminecyclotransferase produces 5-oxo-L-proline and a free alkylamine. Two transcript variants encoding the same protein have been found for this gene.[provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 13-100530281-C-T is Benign according to our data. Variant chr13-100530281-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 310853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00775 (1180/152294) while in subpopulation NFE AF= 0.0126 (854/68020). AF 95% confidence interval is 0.0119. There are 5 homozygotes in gnomad4. There are 563 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCA	NM_000282.4	c.*115C>T		3_prime_UTR_variant	Exon 24 of 24	ENST00000376285.6	NP_000273.2
GGACT	NM_001195087.2	c.*1849G>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000683975.1	NP_001182016.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCA	ENST00000376285.6	c.*115C>T		3_prime_UTR_variant	Exon 24 of 24	1	NM_000282.4	ENSP00000365462.1
GGACT	ENST00000683975	c.*1849G>A		3_prime_UTR_variant	Exon 3 of 3		NM_001195087.2	ENSP00000508020.1

Frequencies

GnomAD3 genomes AF: 0.00775 AC: 1179 AN: 152176 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.00766

GnomAD4 exome AF: 0.00970 AC: 6773 AN: 698160 Hom.: 43 Cov.: 9 AF XY: 0.00943 AC XY: 3483 AN XY: 369250

Gnomad4 AFR exome AF: 0.00171

Gnomad4 AMR exome AF: 0.00639

Gnomad4 ASJ exome AF: 0.00990

Gnomad4 EAS exome AF: 0.0000296

Gnomad4 SAS exome AF: 0.00181

Gnomad4 FIN exome AF: 0.00546

Gnomad4 NFE exome AF: 0.0128

Gnomad4 OTH exome AF: 0.00913

GnomAD4 genome AF: 0.00775 AC: 1180 AN: 152294 Hom.: 5 Cov.: 33 AF XY: 0.00756 AC XY: 563 AN XY: 74464

Gnomad4 AFR AF: 0.00205

Gnomad4 AMR AF: 0.00738

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.0126

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00509 Hom.: 1

Bravo AF: 0.00784

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Propionic acidemia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	11
DANN	Benign	0.77

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: rs41281122; hg19: chr13-101182535;