ENST00000563393.1:c.-136A>G

Variant names:

• chr15-75044388-A-G
• rs2304899
• ENST00000563393.1:c.-136A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000563393.1(PPCDC):​c.-136A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.924 in 1,613,604 control chromosomes in the GnomAD database, including 694,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (55901 hom., cov: 32)
  • Exomes 𝑓: 0.93 (638258 hom.)
• Consequence: PPCDC ENST00000563393.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.74
• Publications: 29 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1492006E-6).
• BP6: Variant 15-75044388-A-G is Benign according to our data. Variant chr15-75044388-A-G is described in ClinVar as Benign. ClinVar VariationId is 1273465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.942 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000563393.1. 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.234A>G	p.Ile78Met	missense splice_region	Exon 4 of 6	NP_068595.3
	PPCDC	NM_001301104.2		c.-136A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	NP_001288033.1	H3BU63
	PPCDC	NM_001301105.2		c.-136A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 5	NP_001288034.1	H3BU63

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPCDC	ENST00000563393.1	TSL:1	c.-136A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000457490.1	H3BU63
	PPCDC	ENST00000342932.8	TSL:1 MANE Select	c.234A>G	p.Ile78Met	missense splice_region	Exon 4 of 6	ENSP00000343190.3	Q96CD2-1
	PPCDC	ENST00000563393.1	TSL:1	c.-136A>G		splice_region	Exon 2 of 4	ENSP00000457490.1	H3BU63

Frequencies

GnomAD3 genomes AF: 0.845 AC: 128524 AN: 152034 Hom.: 55875 Cov.: 32

Gnomad AFR AF: 0.626

Gnomad AMI AF: 0.964

Gnomad AMR AF: 0.852

Gnomad ASJ AF: 0.932

Gnomad EAS AF: 0.876

Gnomad SAS AF: 0.923

Gnomad FIN AF: 0.935

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.948

Gnomad OTH AF: 0.872

GnomAD2 exomes AF: 0.896 AC: 225062 AN: 251164 AF XY: 0.906

Gnomad AFR exome AF: 0.612

Gnomad AMR exome AF: 0.801

Gnomad ASJ exome AF: 0.925

Gnomad EAS exome AF: 0.879

Gnomad FIN exome AF: 0.941

Gnomad NFE exome AF: 0.949

Gnomad OTH exome AF: 0.922

GnomAD4 exome AF: 0.933 AC: 1362986 AN: 1461452 Hom.: 638258 Cov.: 75 AF XY: 0.933 AC XY: 678606 AN XY: 727024

African (AFR) AF: 0.614 AC: 20559 AN: 33468

American (AMR) AF: 0.808 AC: 36139 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.926 AC: 24192 AN: 26126

East Asian (EAS) AF: 0.866 AC: 34368 AN: 39694

South Asian (SAS) AF: 0.924 AC: 79735 AN: 86254

European-Finnish (FIN) AF: 0.939 AC: 49932 AN: 53158

Middle Eastern (MID) AF: 0.938 AC: 5413 AN: 5768

European-Non Finnish (NFE) AF: 0.951 AC: 1057168 AN: 1111894

Other (OTH) AF: 0.919 AC: 55480 AN: 60380

GnomAD4 genome AF: 0.845 AC: 128603 AN: 152152 Hom.: 55901 Cov.: 32 AF XY: 0.848 AC XY: 63066 AN XY: 74386

African (AFR) AF: 0.626 AC: 25955 AN: 41454

American (AMR) AF: 0.852 AC: 13041 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.932 AC: 3236 AN: 3472

East Asian (EAS) AF: 0.876 AC: 4525 AN: 5166

South Asian (SAS) AF: 0.924 AC: 4457 AN: 4826

European-Finnish (FIN) AF: 0.935 AC: 9907 AN: 10600

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.948 AC: 64492 AN: 68012

Other (OTH) AF: 0.870 AC: 1839 AN: 2114

Alfa AF: 0.908 Hom.: 117217

Bravo AF: 0.827

TwinsUK AF: 0.953 AC: 3534

ALSPAC AF: 0.951 AC: 3667

ESP6500AA AF: 0.630 AC: 2769

ESP6500EA AF: 0.947 AC: 8133

ExAC AF: 0.896 AC: 108825

Asia WGS AF: 0.860 AC: 2990 AN: 3478

EpiCase AF: 0.945

EpiControl AF: 0.943

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.76
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.22	N
PhyloP100		3.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.87	N
REVEL	Benign	0.093
Sift	Benign	0.25	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.082
MPC		0.11
ClinPred		0.0050	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.57
Mutation Taster		=74/26	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: rs2304899; hg19: chr15-75336729; COSMIC: COSV61625526; COSMIC: COSV61625526;