Genetic Variant ACADS:p.Leu93Val (chr12-120737052-C-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_000017.4(ACADS):c.277C>G(p.Leu93Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. L93I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

ACADS
NM_000017.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.98

Publications

2 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, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Orphanet, ClinGen

ACADS links:

ENSG00000255946 (HGNC:):

ENSG00000255946 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000017.4

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADS	NM_000017.4 link	c.277C>G	p.Leu93Val	missense_variant	Exon 3 of 10	ENST00000242592.9	NP_000008.1
ACADS	NM_001302554.2 link	c.277C>G	p.Leu93Val	missense_variant	Exon 3 of 10		NP_001289483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ACADS	ENST00000242592.9 link	c.277C>G	p.Leu93Val	missense_variant	Exon 3 of 10	1	NM_000017.4	ENSP00000242592.4
ACADS	ENST00000411593.2 link	c.277C>G	p.Leu93Val	missense_variant	Exon 3 of 10	2		ENSP00000401045.2
ACADS	ENST00000539690.1 link	n.389C>G		non_coding_transcript_exon_variant	Exon 3 of 3	2
ENSG00000255946	ENST00000724268.1 link	n.305-6764G>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000423

AC:

AN:

236320

AF XY:

0.00000781

show subpopulations

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:

0.00000938

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

D;D

Eigen

Benign

0.018

Eigen_PC

Benign

0.046

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Pathogenic

1.2

MutationAssessor

Uncertain

2.4

M;.

PhyloP100

5.0

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.7

D;D

REVEL

Uncertain

0.63

Sift

Benign

0.12

T;T

Sift4G

Benign

0.22

T;T

Vest4

0.65

ClinPred

0.69

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.56

gMVP

0.78

Mutation Taster

=24/76

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over