NM_000017.4:c.511C>T

Variant names:

• chr12-120737875-C-T
• rs1800556
• NM_000017.4:c.511C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000017.4(ACADS):​c.511C>T​(p.Arg171Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0413 in 1,613,908 control chromosomes in the GnomAD database, including 1,595 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (103 hom., cov: 33)
  • Exomes 𝑓: 0.042 (1492 hom.)
• Consequence: ACADS NM_000017.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:8 O:2
• Conservation: PhyloP100: 0.510
• Publications: 54 publications found

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, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Orphanet, ClinGen

ENSG00000255946 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000017.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.58444 (below the threshold of 3.09). Trascript score misZ: 0.78549 (below the threshold of 3.09). GenCC associations: The gene is linked to short chain acyl-CoA dehydrogenase deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.041048765).
• BP6: Variant 12-120737875-C-T is Benign according to our data. Variant chr12-120737875-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 3830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0316 (4805/152176) while in subpopulation NFE AF = 0.0442 (3005/67976). AF 95% confidence interval is 0.0429. There are 103 homozygotes in GnomAd4. There are 2345 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 103 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADS	NM_000017.4	c.511C>T	p.Arg171Trp	missense_variant	Exon 5 of 10	ENST00000242592.9	NP_000008.1
ACADS	NM_001302554.2	c.473-174C>T		intron_variant	Intron 4 of 9		NP_001289483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADS	ENST00000242592.9	c.511C>T	p.Arg171Trp	missense_variant	Exon 5 of 10	1	NM_000017.4	ENSP00000242592.4
ACADS	ENST00000411593.2	c.473-174C>T		intron_variant	Intron 4 of 9	2		ENSP00000401045.2
ENSG00000255946	ENST00000724268.1	n.305-7587G>A		intron_variant	Intron 1 of 1
ACADS	ENST00000539690.1	n.*70C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 4806 AN: 152058 Hom.: 103 Cov.: 33

Gnomad AFR AF: 0.00949

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.0653

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0442

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0309 AC: 7750 AN: 250994 AF XY: 0.0310

Gnomad AFR exome AF: 0.00887

Gnomad AMR exome AF: 0.0169

Gnomad ASJ exome AF: 0.0227

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0636

Gnomad NFE exome AF: 0.0443

Gnomad OTH exome AF: 0.0363

GnomAD4 exome AF: 0.0423 AC: 61903 AN: 1461732 Hom.: 1492 Cov.: 33 AF XY: 0.0414 AC XY: 30070 AN XY: 727170

African (AFR) AF: 0.00792 AC: 265 AN: 33478

American (AMR) AF: 0.0177 AC: 793 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0241 AC: 629 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00692 AC: 597 AN: 86258

European-Finnish (FIN) AF: 0.0625 AC: 3338 AN: 53378

Middle Eastern (MID) AF: 0.0137 AC: 79 AN: 5768

European-Non Finnish (NFE) AF: 0.0485 AC: 53897 AN: 1111908

Other (OTH) AF: 0.0382 AC: 2304 AN: 60386

GnomAD4 genome AF: 0.0316 AC: 4805 AN: 152176 Hom.: 103 Cov.: 33 AF XY: 0.0315 AC XY: 2345 AN XY: 74386

African (AFR) AF: 0.00946 AC: 393 AN: 41540

American (AMR) AF: 0.0331 AC: 507 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4822

European-Finnish (FIN) AF: 0.0653 AC: 691 AN: 10586

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0442 AC: 3005 AN: 67976

Other (OTH) AF: 0.0265 AC: 56 AN: 2110

Alfa AF: 0.0376 Hom.: 492

Bravo AF: 0.0288

TwinsUK AF: 0.0496 AC: 184

ALSPAC AF: 0.0511 AC: 197

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.0465 AC: 400

ExAC AF: 0.0312 AC: 3787

Asia WGS AF: 0.00606 AC: 23 AN: 3478

EpiCase AF: 0.0403

EpiControl AF: 0.0398

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:8 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase Pathogenic:1 Benign:6 Other:2

Jan 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of acyl-CoA dehydrogenase, short-chain, deficiency of (MIM#201470). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

The variant was identified in multiple GenomeConnect participants. Variant interpreted as Uncertain significance and reported on 05-17-2017 by Lab or GTR ID 303161. Variant was interpreted as Pathogenic and reported on 10-02-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jan 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29555771, 29678161, 28532786, 18523805, 9499414, 11134486, 16926354, 12220177) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Benign	-0.056
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.041	T
MetaSVM	Uncertain	0.030	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		0.51
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.29
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.037	D
Polyphen		0.99	D
Vest4		0.15
MPC		0.21
ClinPred		0.063	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.43
gMVP		0.78
Mutation Taster		=75/25	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1800556; hg19: chr12-121175678; COSMIC: COSV54369699; COSMIC: COSV54369699;