dbSNP rs566325901: ACADS:p.Met370Val (chr12-120739317-A-G) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1PP2BP4_StrongBP6BS2_Supporting

The NM_000017.4(ACADS):c.1108A>G(p.Met370Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000906 in 1,613,020 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00054 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00094 ( 17 hom. )

Consequence

ACADS
NM_000017.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:4

Conservation

PhyloP100: 8.96

Publications

7 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:

ENSG00000255946 (HGNC:):

ENSG00000255946 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 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

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=0.028777868).

BP6

Variant 12-120739317-A-G is Benign according to our data. Variant chr12-120739317-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203562.

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.1108A>G	p.Met370Val	missense	Exon 10 of 10	NP_000008.1	P16219
	ACADS	NM_001302554.2		c.1096A>G	p.Met366Val	missense	Exon 10 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.1108A>G	p.Met370Val	missense	Exon 10 of 10	ENSP00000242592.4	P16219
ACADS	ENST00000946559.1		c.1108A>G	p.Met370Val	missense	Exon 10 of 10	ENSP00000616618.1
ACADS	ENST00000893619.1		c.1105A>G	p.Met369Val	missense	Exon 10 of 10	ENSP00000563678.1

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00184

AC:

456

AN:

248156

AF XY:

0.00238

show subpopulations

Gnomad AFR exome

AF:

0.0000639

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000314

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000945

AC:

1380

AN:

1460696

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

945

AN XY:

726652

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33472

American (AMR)

AF:

0.000134

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0128

AC:

1107

AN:

86246

European-Finnish (FIN)

AF:

0.0000955

AC:

AN:

52374

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000169

AC:

188

AN:

1111918

Other (OTH)

AF:

0.000845

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

190

286

381

476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000538

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000805

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41564

American (AMR)

AF:

0.000131

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0145

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.000196

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ExAC

AF:

0.00216

AC:

262

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Deficiency of butyryl-CoA dehydrogenase (4)

not provided (1)

Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.029

MetaSVM

Uncertain

0.66

MutationAssessor

Benign

0.59

PhyloP100

9.0

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.92

Sift

Benign

0.051

Sift4G

Uncertain

0.028

Polyphen

0.82

Vest4

0.95

MVP

0.97

MPC

0.77

ClinPred

0.060

GERP RS

4.7

Varity_R

0.77

gMVP

0.95

Mutation Taster

=19/81

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over