rs566325901

chr12-120739317-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:4
• Conservation: PhyloP100: 8.96

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_benign. Variant got -6 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.028777868).
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADS	NM_000017.4	c.1108A>G	p.Met370Val	missense_variant	10/10	ENST00000242592.9
ACADS	NM_001302554.2	c.1096A>G	p.Met366Val	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADS	ENST00000242592.9	c.1108A>G	p.Met370Val	missense_variant	10/10	1	NM_000017.4	P1
ACADS	ENST00000411593.2	c.1096A>G	p.Met366Val	missense_variant	10/10	2

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152206 Hom.: 2 Cov.: 33

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

GnomAD3 exomes AF: 0.00184 AC: 456 AN: 248156 Hom.: 6 AF XY: 0.00238 AC XY: 321 AN XY: 135010

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 SAS exome AF: 0.0133

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.: 17 Cov.: 33 AF XY: 0.00130 AC XY: 945 AN XY: 726652

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0128

Gnomad4 FIN exome AF: 0.0000955

Gnomad4 NFE exome AF: 0.000169

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.000538 AC: 82 AN: 152324 Hom.: 2 Cov.: 33 AF XY: 0.000805 AC XY: 60 AN XY: 74492

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000372 Hom.: 0

Bravo AF: 0.000196

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ExAC AF: 0.00216 AC: 262

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase Pathogenic:1 Uncertain:2 Benign:2

Likely risk allele, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Potent mutations in ACADS gene can lead to short chain acyl coA dehydrogenase deficiency, which is presents in pediatric age group as one of the fatty acid oxidation disorder. Usually asymptomatic in adults or can present with musculoskeletal symptoms. Carnitine and Riboflavin supplementation have been recommended in some stuides. However, more evidence required to ascertain the role of this variant rs566325901 in short chain acyl coA dehydrogenase deficiency. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 19, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The ACADS c.1108A>G (p.Met370Val) missense variant has been reported in one study in which it is found in a compound heterozygous state in three patients with short-chain acyl-coA dehydrogenase (SCAD) deficiency (Pedersen et al. 2008). The p.Met370Val variant was absent from 100 control alleles but is reported at a frequency of 0.0143 in the South Asian population of the Exome Aggregation Consortium. Functional studies showed that the variant resulted in temperature sensitive decreased tetramer formation and an increased aggregation tendency compared to wild type (Pedersen et al. 2008). The evidence for this variant is limited. The p.Met370Val variant is therefore classified as likely pathogenic for short-chain acyl-coA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Type 2 diabetes mellitus Benign:1

Likely benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The heterozygous p.Met370Val variant in ACADS has been identified in 3 individuals with Acyl-CoA-dehydrogenase deficiency (PMID: 18523805), but has also been identified in >1% of South Asian chromosomes and 6 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Met370Val variant may slightly impact protein function (PMID: 18523805). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for Acyl-CoA-dehydrogenase deficiency. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 15, 2021

This variant is associated with the following publications: (PMID: 27535533, 18523805) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
MetaRNN	Benign	0.029	T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	0.59	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.92
Sift	Benign	0.051	T;D
Sift4G	Uncertain	0.028	D;T
Polyphen		0.82	P;.
Vest4		0.95
MVP		0.97
MPC		0.77
ClinPred		0.060	T
GERP RS		4.7
Varity_R		0.77
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: rs566325901; hg19: chr12-121177120; COSMIC: COSV99656931; COSMIC: COSV99656931;