chr17-42562662-C-A

Variant names:

• chr17-42562662-C-A
• rs1279154386
• NM_025233.7:c.40C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_025233.7(COASY):​c.40C>A​(p.Pro14Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000146 in 1,371,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: COASY NM_025233.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.15

Genes affected

COASY (HGNC:29932): (Coenzyme A synthase) Coenzyme A (CoA) functions as a carrier of acetyl and acyl groups in cells and thus plays an important role in numerous synthetic and degradative metabolic pathways in all organisms. In eukaryotes, CoA and its derivatives are also involved in membrane trafficking and signal transduction. This gene encodes the bifunctional protein coenzyme A synthase (CoAsy) which carries out the last two steps in the biosynthesis of CoA from pantothenic acid (vitamin B5). The phosphopantetheine adenylyltransferase domain of this bifunctional protein catalyzes the conversion of 4'-phosphopantetheine into dephospho-coenzyme A (dpCoA) while its dephospho-CoA kinase domain completes the final step by phosphorylating dpCoA to form CoA. Mutations in this gene are associated with neurodegeneration with brain iron accumulation (NBIA). Alternative splicing results in multiple isoforms. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COASY	NM_025233.7	c.40C>A	p.Pro14Thr	missense_variant	Exon 1 of 9	ENST00000393818.3	NP_079509.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COASY	ENST00000393818.3	c.40C>A	p.Pro14Thr	missense_variant	Exon 1 of 9	1	NM_025233.7	ENSP00000377406.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1371174 Hom.: 0 Cov.: 30 AF XY: 0.00000148 AC XY: 1 AN XY: 673740

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000250

Gnomad4 NFE exome AF: 9.33e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	.;D;T;D;.;D;.;D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D;T;.;D;D;D;D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.1	.;.;.;L;.;.;.;L
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.4	.;.;.;.;.;.;.;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0070	.;.;.;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;.;D;.;.;D;D
Vest4		0.74, 0.74, 0.75
MutPred		0.47		Loss of loop (P = 0.0022);.;Loss of loop (P = 0.0022);Loss of loop (P = 0.0022);.;Loss of loop (P = 0.0022);.;Loss of loop (P = 0.0022);
MVP		0.84
MPC		0.92
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs1279154386; hg19: chr17-40714680;