dbSNP rs28940875: ACADS:p.Arg380Gly (chr12-120739347-C-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000017.4(ACADS):c.1138C>G(p.Arg380Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,716 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. R380W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ACADS
NM_000017.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.61

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-120739347-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADS	NM_000017.4 link	c.1138C>G	p.Arg380Gly	missense_variant	Exon 10 of 10	ENST00000242592.9	NP_000008.1	P16219E5KSD5
ACADS	NM_001302554.2 link	c.1126C>G	p.Arg376Gly	missense_variant	Exon 10 of 10		NP_001289483.1	P16219E9PE82B4DUH1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADS	ENST00000242592.9 link	c.1138C>G	p.Arg380Gly	missense_variant	Exon 10 of 10	1	NM_000017.4	ENSP00000242592.4		P16219
ACADS	ENST00000411593.2 link	c.1126C>G	p.Arg376Gly	missense_variant	Exon 10 of 10	2		ENSP00000401045.2		E9PE82

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248232

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

135028

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000896

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460716

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726664

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

D;D

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;.

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-6.8

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.91

MutPred

0.94

Gain of methylation at R383 (P = 0.0583);.;

MVP

0.99

MPC

0.88

ClinPred

0.98

GERP RS

3.8

Varity_R

0.98

gMVP

0.99

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over