chr12-120738876-C-T

Variant names:

• chr12-120738876-C-T
• rs3915
• NM_000017.4:c.990C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000017.4(ACADS):​c.990C>T​(p.Arg330Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.485 in 1,613,652 control chromosomes in the GnomAD database, including 200,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (29570 hom., cov: 34)
  • Exomes 𝑓: 0.47 (170549 hom.)
• Consequence: ACADS NM_000017.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.49
• Publications: 34 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 12-120738876-C-T is Benign according to our data. Variant chr12-120738876-C-T is described in ClinVar as [Benign]. Clinvar id is 136260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.49 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADS	NM_000017.4	c.990C>T	p.Arg330Arg	synonymous_variant	Exon 8 of 10	ENST00000242592.9	NP_000008.1
ACADS	NM_001302554.2	c.978C>T	p.Arg326Arg	synonymous_variant	Exon 8 of 10		NP_001289483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADS	ENST00000242592.9	c.990C>T	p.Arg330Arg	synonymous_variant	Exon 8 of 10	1	NM_000017.4	ENSP00000242592.4
ACADS	ENST00000411593.2	c.978C>T	p.Arg326Arg	synonymous_variant	Exon 8 of 10	2		ENSP00000401045.2
ENSG00000255946	ENST00000724268.1	n.305-8588G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.592 AC: 90092 AN: 152058 Hom.: 29510 Cov.: 34

Gnomad AFR AF: 0.886

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.591

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.582

GnomAD2 exomes AF: 0.540 AC: 135420 AN: 250796 AF XY: 0.534

Gnomad AFR exome AF: 0.898

Gnomad AMR exome AF: 0.637

Gnomad ASJ exome AF: 0.482

Gnomad EAS exome AF: 0.537

Gnomad FIN exome AF: 0.458

Gnomad NFE exome AF: 0.452

Gnomad OTH exome AF: 0.531

GnomAD4 exome AF: 0.474 AC: 692370 AN: 1461476 Hom.: 170549 Cov.: 70 AF XY: 0.478 AC XY: 347486 AN XY: 727056

African (AFR) AF: 0.905 AC: 30290 AN: 33480

American (AMR) AF: 0.630 AC: 28180 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 12642 AN: 26136

East Asian (EAS) AF: 0.486 AC: 19302 AN: 39700

South Asian (SAS) AF: 0.646 AC: 55755 AN: 86250

European-Finnish (FIN) AF: 0.451 AC: 23913 AN: 53054

Middle Eastern (MID) AF: 0.631 AC: 3637 AN: 5766

European-Non Finnish (NFE) AF: 0.439 AC: 487861 AN: 1111980

Other (OTH) AF: 0.510 AC: 30790 AN: 60388

GnomAD4 genome AF: 0.593 AC: 90205 AN: 152176 Hom.: 29570 Cov.: 34 AF XY: 0.598 AC XY: 44475 AN XY: 74370

African (AFR) AF: 0.887 AC: 36838 AN: 41554

American (AMR) AF: 0.591 AC: 9042 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 1664 AN: 3472

East Asian (EAS) AF: 0.541 AC: 2787 AN: 5154

South Asian (SAS) AF: 0.639 AC: 3082 AN: 4822

European-Finnish (FIN) AF: 0.457 AC: 4841 AN: 10592

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.443 AC: 30139 AN: 67964

Other (OTH) AF: 0.585 AC: 1236 AN: 2114

Alfa AF: 0.509 Hom.: 19178

Bravo AF: 0.614

Asia WGS AF: 0.635 AC: 2205 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Aug 26, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Deficiency of butyryl-CoA dehydrogenase Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.023
DANN	Benign	0.85
PhyloP100		-1.5
Mutation Taster		=100/0	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs3915; hg19: chr12-121176679; COSMIC: COSV54369740; COSMIC: COSV54369740;