Genetic Variant NM_000017.4:c.29_35dupCGGGCCC (chr12-120725913-T-TCGGGCCC) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000017.4(ACADS):c.29_35dupCGGGCCC(p.Ala13GlyfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,404,698 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ACADS
NM_000017.4 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.528

Publications

0 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: Pathogenic. The variant received 11 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 88 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-120725913-T-TCGGGCCC is Pathogenic according to our data. Variant chr12-120725913-T-TCGGGCCC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 553547.Status of the report is no_assertion_criteria_provided, 0 stars.

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.29_35dupCGGGCCC	p.Ala13GlyfsTer10	frameshift	Exon 1 of 10	NP_000008.1	P16219
	ACADS	NM_001302554.2		c.29_35dupCGGGCCC	p.Ala13GlyfsTer10	frameshift	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.29_35dupCGGGCCC	p.Ala13GlyfsTer10	frameshift	Exon 1 of 10	ENSP00000242592.4	P16219
ACADS	ENST00000946559.1		c.29_35dupCGGGCCC	p.Ala13GlyfsTer10	frameshift	Exon 1 of 10	ENSP00000616618.1
ACADS	ENST00000893619.1		c.29_35dupCGGGCCC	p.Ala13GlyfsTer10	frameshift	Exon 1 of 10	ENSP00000563678.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000623

AC:

AN:

160630

AF XY:

0.0000112

show subpopulations

Gnomad AFR exome

AF:

0.000149

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

AF:

7.12e-7

AC:

AN:

1404698

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

696172

show subpopulations

African (AFR)

AF:

0.0000326

AC:

AN:

30692

American (AMR)

AF:

0.00

AC:

AN:

38686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25098

East Asian (EAS)

AF:

0.00

AC:

AN:

36848

South Asian (SAS)

AF:

0.00

AC:

AN:

80632

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36970

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4486

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092746

Other (OTH)

AF:

0.00

AC:

AN:

58540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Deficiency of butyryl-CoA dehydrogenase (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.53

Mutation Taster

=7/193

disease causing (ClinVar)

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over