15-75043533-G-C

Variant names:

• chr15-75043533-G-C
• NM_021823.5:c.228G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021823.5(PPCDC):​c.228G>C​(p.Trp76Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W76R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPCDC NM_021823.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.08
• Publications: 0 publications found

Genes affected

PPCDC (HGNC:28107): (phosphopantothenoylcysteine decarboxylase) Biosynthesis of coenzyme A (CoA) from pantothenic acid (vitamin B5) is an essential universal pathway in prokaryotes and eukaryotes. PPCDC (EC 4.1.1.36), one of the last enzymes in this pathway, converts phosphopantothenoylcysteine to 4-prime-phosphopantetheine (Daugherty et al., 2002 [PubMed 11923312]).[supplied by OMIM, Mar 2008]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021823.5. 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
	PPCDC	NM_021823.5	MANE Select	c.228G>C	p.Trp76Cys	missense	Exon 3 of 6	NP_068595.3
	PPCDC	NM_001301101.2		c.228G>C	p.Trp76Cys	missense	Exon 3 of 5	NP_001288030.1	H3BQB0
	PPCDC	NM_001301104.2		c.-142G>C		5_prime_UTR	Exon 1 of 4	NP_001288033.1	H3BU63

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPCDC	ENST00000342932.8	TSL:1 MANE Select	c.228G>C	p.Trp76Cys	missense	Exon 3 of 6	ENSP00000343190.3	Q96CD2-1
	PPCDC	ENST00000563393.1	TSL:1	c.-142G>C		5_prime_UTR	Exon 1 of 4	ENSP00000457490.1	H3BU63
	PPCDC	ENST00000889947.1		c.228G>C	p.Trp76Cys	missense	Exon 3 of 6	ENSP00000560006.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	-0.070	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		9.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-13	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.019	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.86
MutPred		0.53		Gain of helix (P = 0.132)
MVP		0.88
MPC		0.68
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

hg19: chr15-75335874;