17-42562663-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_025233.7(COASY):c.41C>T(p.Pro14Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,352 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P14A) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: COASY NM_025233.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COASY	NM_025233.7	c.41C>T	p.Pro14Leu	missense_variant	1/9	ENST00000393818.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COASY	ENST00000393818.3	c.41C>T	p.Pro14Leu	missense_variant	1/9	1	NM_025233.7	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000543 AC: 1 AN: 184046 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 98500

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74500

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodegeneration with brain iron accumulation 6 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Feb 14, 2023	The missense variant c.41C>T (p.Pro14Leu) in the COASY gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency (0.0009%) in the gnomAD and novel (not in any individuals) in the 1000 genome database. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Proline at position 14 is changed to a Leucine changing protein sequence and it might alter its composition and physico- chemical properties. The variant is predicted as damaging by SIFT. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 17, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 14 of the COASY protein (p.Pro14Leu). This variant is present in population databases (rs571068316, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with COASY-related conditions. ClinVar contains an entry for this variant (Variation ID: 1992543). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COASY protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;D;D;.;D;D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.74	T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;.;D;.;.;D;D
Vest4		0.78, 0.79, 0.77
MutPred		0.47		Gain of helix (P = 6e-04);.;Gain of helix (P = 6e-04);Gain of helix (P = 6e-04);.;Gain of helix (P = 6e-04);.;Gain of helix (P = 6e-04);
MVP		0.87
MPC		0.88
ClinPred		0.83	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.38
gMVP		0.78

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: rs571068316; hg19: chr17-40714681;