chr12-120737049-G-T

Position:

• chr12-120737049-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000017.4(ACADS):​c.274G>T​(p.Gly92Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 1,608,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ACADS NM_000017.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.94

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 12-120737049-G-T is Pathogenic according to our data. Variant chr12-120737049-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3827.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADS	NM_000017.4	c.274G>T	p.Gly92Cys	missense_variant	3/10	ENST00000242592.9	NP_000008.1
ACADS	NM_001302554.2	c.274G>T	p.Gly92Cys	missense_variant	3/10		NP_001289483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADS	ENST00000242592.9	c.274G>T	p.Gly92Cys	missense_variant	3/10	1	NM_000017.4	ENSP00000242592	P1
ACADS	ENST00000411593.2	c.274G>T	p.Gly92Cys	missense_variant	3/10	2		ENSP00000401045
ACADS	ENST00000539690.1	n.386G>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456044 Hom.: 0 Cov.: 31 AF XY: 0.00000415 AC XY: 3 AN XY: 723720

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74374

Gnomad4 AFR AF: 0.0000724

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 92 of the ACADS protein (p.Gly92Cys). This variant is present in population databases (rs121908004, gnomAD 0.01%). This missense change has been observed in individual(s) with short-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 9499414). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3827). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACADS protein function. Experimental studies have shown that this missense change affects ACADS function (PMID: 9499414, 14506246). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1998	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.7	H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-8.2	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.97		Loss of disorder (P = 0.0446);Loss of disorder (P = 0.0446);
MVP		1.0
MPC		0.74
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.95

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: rs121908004; hg19: chr12-121174852;