Variant chr17-42562662-C-G details in Genebe, Genetics Data Aggregator

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.15

Variant links:

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]

COASY links:

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ACMG classification

Classification made for transcript

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	Protein	UniProt
COASY	NM_025233.7 linkuse as main transcript	c.40C>G	p.Pro14Ala	missense_variant	1/9	ENST00000393818.3	NP_079509.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COASY	ENST00000393818.3 linkuse as main transcript	c.40C>G	p.Pro14Ala	missense_variant	1/9	1	NM_025233.7	ENSP00000377406	P1	Q13057-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183102

Hom.:

AF XY:

0.0000102

AC XY:

AN XY:

97958

show subpopulations

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:

AN:

1371174

Hom.:

Cov.:

AF XY:

0.00000297

AC XY:

AN XY:

673740

show subpopulations

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.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neurodegeneration with brain iron accumulation 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2022

ClinVar contains an entry for this variant (Variation ID: 1419851). 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"). 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.00046

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

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

LIST_S2

Uncertain

0.89

D;D;T;.;D;D;D;D

M_CAP

Benign

0.047

MetaRNN

Uncertain

0.73

D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.1

.;.;.;L;.;.;.;L

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.69

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over