13-100089124-G-T

Variant names:

• chr13-100089124-G-T
• rs760710987
• NM_000282.4:c.4G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000282.4(PCCA):​c.4G>T​(p.Ala2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000741 in 1,349,680 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A2P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: PCCA NM_000282.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.39
• Publications: 0 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-DT (HGNC:53266): (PCCA divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCA	NM_000282.4	MANE Select	c.4G>T	p.Ala2Ser	missense	Exon 1 of 24	NP_000273.2	P05165-1
	PCCA	NM_001352605.2		c.4G>T	p.Ala2Ser	missense	Exon 1 of 23	NP_001339534.1
	PCCA	NM_001127692.3		c.4G>T	p.Ala2Ser	missense	Exon 1 of 23	NP_001121164.1	P05165-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCA	ENST00000376285.6	TSL:1 MANE Select	c.4G>T	p.Ala2Ser	missense	Exon 1 of 24	ENSP00000365462.1	P05165-1
	PCCA	ENST00000881637.1		c.4G>T	p.Ala2Ser	missense	Exon 1 of 25	ENSP00000551696.1
	PCCA	ENST00000881640.1		c.4G>T	p.Ala2Ser	missense	Exon 1 of 25	ENSP00000551699.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.41e-7 AC: 1 AN: 1349680 Hom.: 0 Cov.: 31 AF XY: 0.00000151 AC XY: 1 AN XY: 661722

African (AFR) AF: 0.00 AC: 0 AN: 28458

American (AMR) AF: 0.00 AC: 0 AN: 32464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23604

East Asian (EAS) AF: 0.00 AC: 0 AN: 32464

South Asian (SAS) AF: 0.00 AC: 0 AN: 72416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45678

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4902

European-Non Finnish (NFE) AF: 9.49e-7 AC: 1 AN: 1053986

Other (OTH) AF: 0.00 AC: 0 AN: 55708

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.73	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.90	L
PhyloP100		3.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.57	N
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.39
MutPred		0.29		Gain of glycosylation at A2 (P = 0.0323)
MVP		0.96
MPC		0.13
ClinPred		0.82	D
GERP RS		4.8
PromoterAI		-0.58	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.33
Mutation Taster		=83/17	polymorphism

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: rs760710987; hg19: chr13-100741378;