1-42456576-T-A

Variant names:

• chr1-42456576-T-A
• rs547431390
• NM_024664.4:c.11T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024664.4(PPCS):​c.11T>A​(p.Met4Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000751 in 1,331,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. M4T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: PPCS NM_024664.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.561
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031034559).

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.11T>A	p.Met4Lys	missense	Exon 1 of 3	NP_078940.2	Q9HAB8-1
	PPCS	NM_001287511.2		c.11T>A	p.Met4Lys	missense	Exon 1 of 3	NP_001274440.1
	PPCS	NM_001077447.3		c.-64T>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.11T>A	p.Met4Lys	missense	Exon 1 of 3	ENSP00000361642.3	Q9HAB8-1
	PPCS	ENST00000372560.3	TSL:1	c.11T>A	p.Met4Lys	missense	Exon 1 of 2	ENSP00000361641.3	Q5VVM3
	PPCS	ENST00000472013.1	TSL:1	n.33T>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.51e-7 AC: 1 AN: 1331984 Hom.: 0 Cov.: 31 AF XY: 0.00000154 AC XY: 1 AN XY: 650132

African (AFR) AF: 0.00 AC: 0 AN: 28854

American (AMR) AF: 0.00 AC: 0 AN: 22578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19088

East Asian (EAS) AF: 0.00 AC: 0 AN: 36028

South Asian (SAS) AF: 0.00 AC: 0 AN: 68168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5208

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1051124

Other (OTH) AF: 0.0000183 AC: 1 AN: 54746

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000867 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.88
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.56
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.64	N
REVEL	Benign	0.081
Sift	Benign	0.68	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.30
MutPred		0.25		Gain of ubiquitination at M4 (P = 0.0031)
MVP		0.16
MPC		0.99
ClinPred		0.036	T
GERP RS		-3.0
PromoterAI		-0.37	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.42
gMVP		0.41
Mutation Taster		=91/9	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: rs547431390; hg19: chr1-42922247;