Genetic Variant ACADS:p.Arg14Leu (chr12-120725926-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_000017.4(ACADS):c.41G>T(p.Arg14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. R14H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACADS
NM_000017.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.832

Publications

1 publications found

Variant links:

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)

ACADS links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.33114034).

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.41G>T	p.Arg14Leu	missense	Exon 1 of 10	NP_000008.1	P16219
	ACADS	NM_001302554.2		c.41G>T	p.Arg14Leu	missense	Exon 1 of 10	NP_001289483.1	E9PE82

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACADS	ENST00000242592.9	TSL:1 MANE Select	c.41G>T	p.Arg14Leu	missense	Exon 1 of 10	ENSP00000242592.4	P16219
ACADS	ENST00000946559.1		c.41G>T	p.Arg14Leu	missense	Exon 1 of 10	ENSP00000616618.1
ACADS	ENST00000893619.1		c.41G>T	p.Arg14Leu	missense	Exon 1 of 10	ENSP00000563678.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

153224

AF XY:

0.00

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:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1400094

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

693564

African (AFR)

AF:

0.00

AC:

AN:

30438

American (AMR)

AF:

0.00

AC:

AN:

38092

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24978

East Asian (EAS)

AF:

0.00

AC:

AN:

36518

South Asian (SAS)

AF:

0.00

AC:

AN:

80196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4370

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090502

Other (OTH)

AF:

0.00

AC:

AN:

58370

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.42

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.64

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.33

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

0.0

PhyloP100

0.83

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.43

Sift

Uncertain

0.021

Sift4G

Benign

0.067

Polyphen

0.032

Vest4

0.35

MutPred

0.55

Loss of disorder (P = 0.0362)

MVP

0.87

MPC

0.24

ClinPred

0.19

GERP RS

3.1

PromoterAI

0.073

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.11

gMVP

0.50

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over