13-100368573-C-G

Variant names:

• chr13-100368573-C-G
• rs16957356
• NM_000282.4:c.1745C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000282.4(PCCA):​c.1745C>G​(p.Ser582Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. S582L) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: PCCA NM_000282.4 missense, splice_region
• Scores: Splicing: ADA: 0.0004734
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.397
• Publications: 10 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24435207).

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.1745C>G	p.Ser582Trp	missense splice_region	Exon 19 of 24	NP_000273.2
	PCCA	NM_001352605.2		c.1745C>G	p.Ser582Trp	missense splice_region	Exon 19 of 23	NP_001339534.1
	PCCA	NM_001127692.3		c.1667C>G	p.Ser556Trp	missense splice_region	Exon 18 of 23	NP_001121164.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCA	ENST00000376285.6	TSL:1 MANE Select	c.1745C>G	p.Ser582Trp	missense splice_region	Exon 19 of 24	ENSP00000365462.1
	PCCA	ENST00000881637.1		c.1868C>G	p.Ser623Trp	missense splice_region	Exon 20 of 25	ENSP00000551696.1
	PCCA	ENST00000881640.1		c.1850C>G	p.Ser617Trp	missense splice_region	Exon 20 of 25	ENSP00000551699.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151694 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251170 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 24

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151694 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74050

African (AFR) AF: 0.0000242 AC: 1 AN: 41278

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67926

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 51

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.40
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.044	D
Polyphen		0.95	P
Vest4		0.51
MutPred		0.47		Loss of disorder (P = 0.0085)
MVP		0.71
MPC		0.47
ClinPred		0.70	D
GERP RS		0.53
PromoterAI		-0.021	Neutral
Varity_R		0.085
gMVP		0.67
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00047
dbscSNV1_RF	Benign	0.030
SpliceAI score (max)		0.080		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: rs16957356; hg19: chr13-101020827; COSMIC: COSV66188168;