NM_025233.7:c.932C>T

Variant names:

• chr17-42564462-C-T
• rs201949834
• NM_025233.7:c.932C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_025233.7(COASY):​c.932C>T​(p.Ala311Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00038 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: COASY NM_025233.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.25
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• neurodegeneration with brain iron accumulation 6

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• pontocerebellar hypoplasia, type 12

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07928941).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025233.7. 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
	COASY	NM_025233.7	MANE Select	c.932C>T	p.Ala311Val	missense	Exon 3 of 9	NP_079509.5
	COASY	NM_001042532.4		c.1019C>T	p.Ala340Val	missense	Exon 5 of 11	NP_001035997.2	Q13057-2
	COASY	NM_001042529.3		c.932C>T	p.Ala311Val	missense	Exon 4 of 10	NP_001035994.1	Q13057-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COASY	ENST00000393818.3	TSL:1 MANE Select	c.932C>T	p.Ala311Val	missense	Exon 3 of 9	ENSP00000377406.1	Q13057-1
	COASY	ENST00000590958.5	TSL:1	c.1019C>T	p.Ala340Val	missense	Exon 5 of 11	ENSP00000464814.1	Q13057-2
	COASY	ENST00000421097.6	TSL:1	c.932C>T	p.Ala311Val	missense	Exon 4 of 10	ENSP00000393564.2	Q13057-1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152140 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000207 AC: 52 AN: 251450 AF XY: 0.000177

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000404

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000401 AC: 586 AN: 1461846 Hom.: 0 Cov.: 33 AF XY: 0.000391 AC XY: 284 AN XY: 727222

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.000375 AC: 20 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000496 AC: 552 AN: 1111990

Other (OTH) AF: 0.000182 AC: 11 AN: 60392

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152140 Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 15 AN XY: 74328

African (AFR) AF: 0.0000483 AC: 2 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.000170

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000218

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Neurodegeneration with brain iron accumulation 6 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.079	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	-0.085	N
PhyloP100		2.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.24
Sift	Benign	1.0	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.057
MVP		0.94
MPC		0.24
ClinPred		0.087	T
GERP RS		5.1
Varity_R		0.071
gMVP		0.41
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs201949834; hg19: chr17-40716480;