rs387906308

Positions:

• chr12-120737080-TGGA-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_000017.4(ACADS):​c.310_312delGAG​(p.Glu104del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00003 in 1,602,384 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: ACADS NM_000017.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.77

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000017.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 12-120737080-TGGA-T is Pathogenic according to our data. Variant chr12-120737080-TGGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 3833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-120737080-TGGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADS	NM_000017.4	c.310_312delGAG	p.Glu104del	conservative_inframe_deletion	3/10	ENST00000242592.9	NP_000008.1
ACADS	NM_001302554.2	c.310_312delGAG	p.Glu104del	conservative_inframe_deletion	3/10		NP_001289483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADS	ENST00000242592.9	c.310_312delGAG	p.Glu104del	conservative_inframe_deletion	3/10	1	NM_000017.4	ENSP00000242592.4
ACADS	ENST00000411593.2	c.310_312delGAG	p.Glu104del	conservative_inframe_deletion	3/10	2		ENSP00000401045.2
ACADS	ENST00000539690.1	n.422_424delGAG		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.0000221 AC: 5 AN: 226670 Hom.: 0 AF XY: 0.0000244 AC XY: 3 AN XY: 122754

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: 0.0000395

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.0000310 AC: 45 AN: 1450142 Hom.: 0 AF XY: 0.0000361 AC XY: 26 AN XY: 720232

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: 0.0000361

Gnomad4 OTH exome AF: 0.0000834

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74384

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 17, 2023	Experimental studies have shown that this variant affects ACADS function (PMID: 11134486). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 3833). This variant has been observed in individuals with short-chain acyl-CoA dehydrogenase deficiency (PMID: 11134486, 26110041, 29678161). This variant is present in population databases (rs751780151, gnomAD 0.003%). This variant, c.310_312del, results in the deletion of 1 amino acid(s) of the ACADS protein (p.Glu104del), but otherwise preserves the integrity of the reading frame. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 24, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Feb 20, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PS3,PM3. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 30, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2014	The c.310_312delGAG mutation in the ACADS gene has been reported previously in association with short chain acyl-CoA dehydrogenase (SCAD) deficiency in an individual who also harbored the common G209S variant and in whom fibroblast SCAD activity was undetectable (Corydon et al., 2001). The deletion results in the loss of a single Glutamic Acid at codon 104, denoted p.Glu104del. The surrounding sequence GGAG{delGAG}ATCA. The variant is found in ACADS panel(s). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs387906308; hg19: chr12-121174883;