chr12-120737094-C-T

Variant names:

• chr12-120737094-C-T
• rs61732144
• NM_000017.4:c.319C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 22P and 2B. PS1 PS3 PM1 PM5 PP2 PP3 PP5_Very_Strong BP4 BS2_Supporting

The NM_000017.4(ACADS):​c.319C>T​(p.Arg107Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000502 in 1,597,502 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000376674: Schmidt et al. (2011) and Zolkipli et al. (2011) each studied functional consequences of the p.Arg107Cys variant both in homozygous and compound heterozygous states, and demonstrated protein misfolding, reduced activity, and decreased resistance to oxidative stress in cell model systems and cultured patient cells." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R107H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00053 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (7 hom.)
• Consequence: ACADS NM_000017.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 1.47
• Publications: 28 publications found

Genes affected

ACADS (HGNC:90): (acyl-CoA dehydrogenase short chain) This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Mutations in this gene have been associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency. Alternative splicing results in two variants which encode different isoforms. [provided by RefSeq, Oct 2014]

ACADS Gene-Disease associations (from GenCC):

• short chain acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000255946 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS1: Transcript NM_000017.4 (ACADS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000376674: Schmidt et al. (2011) and Zolkipli et al. (2011) each studied functional consequences of the p.Arg107Cys variant both in homozygous and compound heterozygous states, and demonstrated protein misfolding, reduced activity, and decreased resistance to oxidative stress in cell model systems and cultured patient cells.; SCV000632503: Experimental studies have shown that this missense change affects ACADS function (PMID: 18523805, 21170680, 24485985).; SCV000711743: "In vitro functional studies provide some evidence that the p.Arg107Cys variant may impact protein function (Tein 2008, Schmidt 2011, Edhager 2014)."; SCV001142437: Functional studies demonstrate that p.Arg107Cys give rise to inactive misfolded protein species, eliciting a mild toxic response manifested though a decreased proliferation rate and oxidative stress (PMID: 21170680).; SCV004028617: "Several publications report experimental evidence evaluating an impact on protein function, finding that the variant leads to a severe protein folding defect, the inability to produce homotetramers, and increased protein aggregation and chaperone complex formation (e.g., Tein_2008, Schmidt_2011, Pedersen_2008)."; SCV000238601: Expression studies found that R107C is associated with no residual short chain acyl-CoA dehydrogenase activity (Schmidt et al. 2011);; SCV003544261: "In vitro functional expression studies showed that the c.319C>T mutant protein was unable to form a functional tetramer resulting in a decreased amount of SCAD protein, loss of enzyme activity, and increased oxidative stress (Tein, 2008; Schmidt, 2011; Edhager, 2014)."
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000017.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-120737095-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3574271.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.58444 (below the threshold of 3.09). Trascript score misZ: 0.78549 (below the threshold of 3.09). GenCC associations: The gene is linked to short chain acyl-CoA dehydrogenase deficiency.
• PP3: Multiple lines of computational evidence support a deleterious effect 9: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]
• PP5: Variant 12-120737094-C-T is Pathogenic according to our data. Variant chr12-120737094-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.058556437). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000017.4. 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
	ACADS	NM_000017.4	MANE Select	c.319C>T	p.Arg107Cys	missense	Exon 3 of 10	NP_000008.1	P16219
	ACADS	NM_001302554.2		c.319C>T	p.Arg107Cys	missense	Exon 3 of 10	NP_001289483.1	E9PE82

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADS	ENST00000242592.9	TSL:1 MANE Select	c.319C>T	p.Arg107Cys	missense	Exon 3 of 10	ENSP00000242592.4	P16219
	ACADS	ENST00000946559.1		c.319C>T	p.Arg107Cys	missense	Exon 3 of 10	ENSP00000616618.1
	ACADS	ENST00000893619.1		c.319C>T	p.Arg107Cys	missense	Exon 3 of 10	ENSP00000563678.1

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152246 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000970 AC: 213 AN: 219678 AF XY: 0.000901

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000629

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000537

Gnomad NFE exome AF: 0.000216

Gnomad OTH exome AF: 0.00145

GnomAD4 exome AF: 0.000499 AC: 721 AN: 1445256 Hom.: 7 Cov.: 31 AF XY: 0.000506 AC XY: 363 AN XY: 717420

African (AFR) AF: 0.0000301 AC: 1 AN: 33236

American (AMR) AF: 0.0000937 AC: 4 AN: 42682

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 488 AN: 25704

East Asian (EAS) AF: 0.00 AC: 0 AN: 39084

South Asian (SAS) AF: 0.0000718 AC: 6 AN: 83534

European-Finnish (FIN) AF: 0.0000580 AC: 3 AN: 51748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.000116 AC: 128 AN: 1103814

Other (OTH) AF: 0.00152 AC: 91 AN: 59708

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152246 Hom.: 2 Cov.: 33 AF XY: 0.000605 AC XY: 45 AN XY: 74386

African (AFR) AF: 0.0000241 AC: 1 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68040

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000938 Hom.: 0

Bravo AF: 0.000586

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000786 AC: 95

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	-	-	Deficiency of butyryl-CoA dehydrogenase (14)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.059	T
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		1.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MVP		1.0
MPC		0.91
ClinPred		0.51	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.96
Mutation Taster		=17/83	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs61732144; hg19: chr12-121174897;