12-120739362-G-T

Variant names:

• chr12-120739362-G-T
• rs202124189
• NM_000017.4:c.1153G>T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_000017.4(ACADS):​c.1153G>T​(p.Ala385Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,020 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (2 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ACADS NM_000017.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 9.61

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 -1 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADS	NM_000017.4	c.1153G>T	p.Ala385Ser	missense_variant	Exon 10 of 10	ENST00000242592.9	NP_000008.1
ACADS	NM_001302554.2	c.1141G>T	p.Ala381Ser	missense_variant	Exon 10 of 10		NP_001289483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADS	ENST00000242592.9	c.1153G>T	p.Ala385Ser	missense_variant	Exon 10 of 10	1	NM_000017.4	ENSP00000242592.4
ACADS	ENST00000411593.2	c.1141G>T	p.Ala381Ser	missense_variant	Exon 10 of 10	2		ENSP00000401045.2

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152222 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

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: 0.00

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 248180 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 135036

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1460680 Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9 AN XY: 726658

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

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: 0.000116

GnomAD4 genome AF: 0.000203 AC: 31 AN: 152340 Hom.: 2 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74502

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000945

Bravo AF: 0.000416

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 385 of the ACADS protein (p.Ala385Ser). This variant is present in population databases (rs202124189, gnomAD 0.01%). This missense change has been observed in individuals with biochemical features of short-chain acyl-coenzyme A dehydrogenase deficiency (internal data). ClinVar contains an entry for this variant (Variation ID: 379779). Invitae Evidence 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 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. This variant disrupts the p.Ala385 amino acid residue in ACADS. Other variant(s) that disrupt this residue have been observed in individuals with ACADS-related conditions (internal data), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

May 02, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Feb 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1153G>T (p.A385S) alteration is located in exon 10 (coding exon 10) of the ACADS gene. This alteration results from a G to T substitution at nucleotide position 1153, causing the alanine (A) at amino acid position 385 to be replaced by a serine (S). Based on data from gnomAD, the T allele has an overall frequency of 0.002% (5/248180) total alleles studied. This alteration was detected in an individual with elevations in C4 acylcarnitines and ethylmalonic aciduria in combination with homozygous ACADS c.625G>A, a common variant that is not thought to be causative of short-chain acyl-CoA dehydrogenase deficiency (Pena, 2012). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Mar 02, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32778825, 22241096) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.024	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.98	D;.
Vest4		0.90
MVP		0.98
MPC		0.73
ClinPred		0.85	D
GERP RS		4.7
Varity_R		0.68
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: rs202124189; hg19: chr12-121177165;