17-42562662-C-G

Variant names:

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

Variant summary

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

The NM_025233.7(COASY):​c.40C>G​(p.Pro14Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000219 in 1,371,174 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: COASY NM_025233.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 rank	MANE	Protein	UniProt
COASY	NM_025233.7	c.40C>G	p.Pro14Ala	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>G	p.Pro14Ala	missense_variant	Exon 1 of 9	1	NM_025233.7	ENSP00000377406.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183102 Hom.: 0 AF XY: 0.0000102 AC XY: 1 AN XY: 97958

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000420

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1371174 Hom.: 0 Cov.: 30 AF XY: 0.00000297 AC XY: 2 AN XY: 673740

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000612

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.33e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodegeneration with brain iron accumulation 6 Uncertain:1

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with COASY-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 14 of the COASY protein (p.Pro14Ala). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1419851). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.00046	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	.;T;T;T;.;T;.;T
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;T;.;D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.1	.;.;.;L;.;.;.;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.5	.;.;.;.;.;.;.;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.013	.;.;.;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		0.96, 1.0	.;.;.;D;.;.;D;D
Vest4		0.63, 0.63, 0.63
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		0.83
MPC		0.85
ClinPred		0.89	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.62

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;