rs372649775

Variant names:

• chr3-136250342-G-A
• rs372649775
• NM_000532.5:c.-34G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-136250342-G-A
• chr3-136250342-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000532.5(PCCB):​c.-34G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000412 in 1,483,054 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00068 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: PCCB NM_000532.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.337
• Publications: 0 publications found

Genes affected

PCCB (HGNC:8654): (propionyl-CoA carboxylase subunit beta) The protein encoded by this gene is a subunit of the propionyl-CoA carboxylase (PCC) enzyme, which is involved in the catabolism of propionyl-CoA. PCC is a mitochondrial enzyme that probably acts as a dodecamer of six alpha subunits and six beta subunits. This gene encodes the beta subunit of PCC. Defects in this gene are a cause of propionic acidemia type II (PA-2). Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

PCCB Gene-Disease associations (from GenCC):

• propionic acidemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCB	NM_000532.5	c.-34G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 15	ENST00000251654.9	NP_000523.2
PCCB	NM_000532.5	c.-34G>A		5_prime_UTR_variant	Exon 1 of 15	ENST00000251654.9	NP_000523.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9	c.-34G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 15	1	NM_000532.5	ENSP00000251654.4
PCCB	ENST00000251654.9	c.-34G>A		5_prime_UTR_variant	Exon 1 of 15	1	NM_000532.5	ENSP00000251654.4

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152240 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00602

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000852 AC: 87 AN: 102146 AF XY: 0.000660

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000560

Gnomad ASJ exome AF: 0.00138

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00528

Gnomad NFE exome AF: 0.000570

Gnomad OTH exome AF: 0.000353

GnomAD4 exome AF: 0.000382 AC: 508 AN: 1330814 Hom.: 1 Cov.: 31 AF XY: 0.000344 AC XY: 223 AN XY: 648482

African (AFR) AF: 0.0000336 AC: 1 AN: 29758

American (AMR) AF: 0.000106 AC: 3 AN: 28344

Ashkenazi Jewish (ASJ) AF: 0.00179 AC: 37 AN: 20662

East Asian (EAS) AF: 0.00 AC: 0 AN: 35084

South Asian (SAS) AF: 0.0000145 AC: 1 AN: 68874

European-Finnish (FIN) AF: 0.00504 AC: 227 AN: 45024

Middle Eastern (MID) AF: 0.000224 AC: 1 AN: 4460

European-Non Finnish (NFE) AF: 0.000205 AC: 214 AN: 1043744

Other (OTH) AF: 0.000437 AC: 24 AN: 54864

GnomAD4 genome AF: 0.000677 AC: 103 AN: 152240 Hom.: 1 Cov.: 33 AF XY: 0.000888 AC XY: 66 AN XY: 74366

African (AFR) AF: 0.0000241 AC: 1 AN: 41480

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00602 AC: 64 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68040

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Propionic acidemia Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.7
DANN	Benign	0.85
PhyloP100		-0.34
PromoterAI		0.20	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs372649775; hg19: chr3-135969184;