rs532174593

Variant names:

• chr12-120738355-C-G
• rs532174593
• NM_000017.4:c.700C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-120738355-C-G
• chr12-120738355-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000017.4(ACADS):​c.700C>G​(p.Arg234Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R234W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ACADS NM_000017.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.81
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics, PanelApp Australia, Orphanet

ENSG00000255946 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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: MetaRNN computational evidence supports a deleterious effect, 0.811

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.700C>G	p.Arg234Gly	missense	Exon 6 of 10	NP_000008.1	P16219
	ACADS	NM_001302554.2		c.688C>G	p.Arg230Gly	missense	Exon 6 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.700C>G	p.Arg234Gly	missense	Exon 6 of 10	ENSP00000242592.4	P16219
	ACADS	ENST00000946559.1		c.700C>G	p.Arg234Gly	missense	Exon 6 of 10	ENSP00000616618.1
	ACADS	ENST00000893619.1		c.700C>G	p.Arg234Gly	missense	Exon 6 of 10	ENSP00000563678.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251384 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461824 Hom.: 0 Cov.: 42 AF XY: 0.0000124 AC XY: 9 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53352

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		2.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.46	P
Vest4		0.86
MutPred		0.53		Loss of phosphorylation at S237 (P = 0.0803)
MVP		0.99
MPC		0.74
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.97
gMVP		0.97
Mutation Taster		=26/74	disease causing

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: rs532174593; hg19: chr12-121176158;