NM_000282.4:c.468+8498A>G

Variant names:

• chr13-100165838-A-G
• rs2184971
• NM_000282.4:c.468+8498A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000282.4(PCCA):​c.468+8498A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 151,874 control chromosomes in the GnomAD database, including 19,280 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (19280 hom., cov: 31)
• Consequence: PCCA NM_000282.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.76
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.753 is higher than 0.05.

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.468+8498A>G		intron	N/A	NP_000273.2
	PCCA	NM_001352605.2		c.468+8498A>G		intron	N/A	NP_001339534.1
	PCCA	NM_001127692.3		c.390+8498A>G		intron	N/A	NP_001121164.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCA	ENST00000376285.6	TSL:1 MANE Select	c.468+8498A>G		intron	N/A	ENSP00000365462.1
	PCCA	ENST00000881637.1		c.468+8498A>G		intron	N/A	ENSP00000551696.1
	PCCA	ENST00000881640.1		c.468+8498A>G		intron	N/A	ENSP00000551699.1

Frequencies

GnomAD3 genomes AF: 0.495 AC: 75137 AN: 151756 Hom.: 19248 Cov.: 31

Gnomad AFR AF: 0.549

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.774

Gnomad SAS AF: 0.689

Gnomad FIN AF: 0.487

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.445

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

GnomAD4 genome AF: 0.495 AC: 75222 AN: 151874 Hom.: 19280 Cov.: 31 AF XY: 0.503 AC XY: 37329 AN XY: 74212

African (AFR) AF: 0.550 AC: 22749 AN: 41384

American (AMR) AF: 0.499 AC: 7617 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1280 AN: 3470

East Asian (EAS) AF: 0.773 AC: 3994 AN: 5164

South Asian (SAS) AF: 0.687 AC: 3303 AN: 4808

European-Finnish (FIN) AF: 0.487 AC: 5118 AN: 10508

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.437 AC: 29702 AN: 67956

Other (OTH) AF: 0.447 AC: 943 AN: 2110

Alfa AF: 0.464 Hom.: 2668

Bravo AF: 0.494

Asia WGS AF: 0.720 AC: 2502 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.56
DANN	Benign	0.33
PhyloP100		-1.8
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

Other links and lift over

dbSNP: rs2184971; hg19: chr13-100818092;