17-42562647-C-T

Position:

• chr17-42562647-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_025233.7(COASY):​c.25C>T​(p.Leu9=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,522,404 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (23 hom.)
• Consequence: COASY NM_025233.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.77

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 17-42562647-C-T is Benign according to our data. Variant chr17-42562647-C-T is described in ClinVar as [Benign]. Clinvar id is 517020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42562647-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00273 (416/152358) while in subpopulation SAS AF= 0.0128 (62/4832). AF 95% confidence interval is 0.0103. There are 1 homozygotes in gnomad4. There are 235 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COASY	NM_025233.7	c.25C>T	p.Leu9=	synonymous_variant	1/9	ENST00000393818.3	NP_079509.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COASY	ENST00000393818.3	c.25C>T	p.Leu9=	synonymous_variant	1/9	1	NM_025233.7	ENSP00000377406	P1

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 414 AN: 152240 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00347 AC: 629 AN: 181096 Hom.: 4 AF XY: 0.00385 AC XY: 372 AN XY: 96720

Gnomad AFR exome AF: 0.000590

Gnomad AMR exome AF: 0.00222

Gnomad ASJ exome AF: 0.00400

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0104

Gnomad FIN exome AF: 0.00250

Gnomad NFE exome AF: 0.00355

Gnomad OTH exome AF: 0.00629

GnomAD4 exome AF: 0.00377 AC: 5161 AN: 1370046 Hom.: 23 Cov.: 30 AF XY: 0.00394 AC XY: 2651 AN XY: 673140

Gnomad4 AFR exome AF: 0.000520

Gnomad4 AMR exome AF: 0.00202

Gnomad4 ASJ exome AF: 0.00304

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.00256

Gnomad4 NFE exome AF: 0.00353

Gnomad4 OTH exome AF: 0.00411

GnomAD4 genome AF: 0.00273 AC: 416 AN: 152358 Hom.: 1 Cov.: 32 AF XY: 0.00315 AC XY: 235 AN XY: 74494

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.00287

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0128

Gnomad4 FIN AF: 0.00376

Gnomad4 NFE AF: 0.00329

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00317 Hom.: 1

Bravo AF: 0.00218

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	COASY: BP4, BP7, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 22, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Neurodegeneration with brain iron accumulation 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.4
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs117419466; hg19: chr17-40714665; COSMIC: COSV99888984; COSMIC: COSV99888984;