1-42456588-C-A

Variant names:

• chr1-42456588-C-A
• rs1643192356
• NM_024664.4:c.23C>A

Variant summary

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

The NM_024664.4(PPCS):​c.23C>A​(p.Ala8Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000743 in 1,346,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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. A8S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: PPCS NM_024664.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.14
• Publications: 0 publications found

Genes affected

PPCS (HGNC:25686): (phosphopantothenoylcysteine synthetase) Biosynthesis of coenzyme A (CoA) from pantothenic acid (vitamin B5) is an essential universal pathway in prokaryotes and eukaryotes. PPCS (EC 6.3.2.5), one of the last enzymes in this pathway, converts phosphopantothenate to phosphopantothenoylcysteine (Daugherty et al., 2002 [PubMed 11923312]).[supplied by OMIM, Mar 2008]

CCDC30 (HGNC:26103): (coiled-coil domain containing 30)

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=0.13983777).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024664.4. 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
	PPCS	NM_024664.4	MANE Select	c.23C>A	p.Ala8Asp	missense	Exon 1 of 3	NP_078940.2	Q9HAB8-1
	PPCS	NM_001287511.2		c.23C>A	p.Ala8Asp	missense	Exon 1 of 3	NP_001274440.1
	PPCS	NM_001077447.3		c.-52C>A		5_prime_UTR	Exon 1 of 3	NP_001070915.1	Q9HAB8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPCS	ENST00000372561.4	TSL:1 MANE Select	c.23C>A	p.Ala8Asp	missense	Exon 1 of 3	ENSP00000361642.3	Q9HAB8-1
	PPCS	ENST00000372560.3	TSL:1	c.23C>A	p.Ala8Asp	missense	Exon 1 of 2	ENSP00000361641.3	Q5VVM3
	PPCS	ENST00000472013.1	TSL:1	n.45C>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.43e-7 AC: 1 AN: 1346280 Hom.: 0 Cov.: 31 AF XY: 0.00000152 AC XY: 1 AN XY: 658310

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29422

American (AMR) AF: 0.00 AC: 0 AN: 25126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19494

East Asian (EAS) AF: 0.00 AC: 0 AN: 37054

South Asian (SAS) AF: 0.0000144 AC: 1 AN: 69488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5264

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1057962

Other (OTH) AF: 0.00 AC: 0 AN: 55260

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.078
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.28	T
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.14		Gain of solvent accessibility (P = 0.1708)
MVP		0.31
MPC		1.0
ClinPred		0.77	D
GERP RS		5.3
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.39
gMVP		0.53
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1643192356; hg19: chr1-42922259;