3-136326880-ACT-TCA

Variant names:

• chr3-136326880-ACT-TCA
• NM_000532.5:c.1168_1170delACTinsTCA
• PCCB p.Thr390Ser

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP2 PP3

The NM_000532.5(PCCB):​c.1168_1170delACTinsTCA​(p.Thr390Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T390I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCCB NM_000532.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.64
• 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: Myriad Women’s Health, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000532.5
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 61 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: -0.86701 (below the threshold of 3.09). Trascript score misZ: -0.97134 (below the threshold of 3.09). GenCC associations: The gene is linked to propionic acidemia.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000532.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCB	NM_000532.5	MANE Select	c.1168_1170delACTinsTCA	p.Thr390Ser	missense	N/A	NP_000523.2	P05166-1
	PCCB	NM_001178014.2		c.1228_1230delACTinsTCA	p.Thr410Ser	missense	N/A	NP_001171485.1	P05166-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCB	ENST00000251654.9	TSL:1 MANE Select	c.1168_1170delACTinsTCA	p.Thr390Ser	missense	N/A	ENSP00000251654.4	P05166-1
	PCCB	ENST00000471595.5	TSL:1	c.1168_1170delACTinsTCA	p.Thr390Ser	missense	N/A	ENSP00000417549.1	E9PDR0
	PCCB	ENST00000478469.5	TSL:1	c.885-7400_885-7398delACTinsTCA		intron	N/A	ENSP00000420759.1	E7ENC1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.6

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-136045722;