12-120737096-T-C

Variant names:

• chr12-120737096-T-C
• rs3914
• NM_000017.4:c.321T>C

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.321T>C​(p.Arg107Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 1,593,530 control chromosomes in the GnomAD database, including 182,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21302 hom., cov: 35)
  • Exomes 𝑓: 0.47 (160839 hom.)
• Consequence: ACADS NM_000017.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.176
• Publications: 33 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=-0.64).
• BP6: Variant 12-120737096-T-C is Benign according to our data. Variant chr12-120737096-T-C is described in ClinVar as Benign. ClinVar VariationId is 136259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.176 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADS	NM_000017.4	c.321T>C	p.Arg107Arg	synonymous_variant	Exon 3 of 10	ENST00000242592.9	NP_000008.1
ACADS	NM_001302554.2	c.321T>C	p.Arg107Arg	synonymous_variant	Exon 3 of 10		NP_001289483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADS	ENST00000242592.9	c.321T>C	p.Arg107Arg	synonymous_variant	Exon 3 of 10	1	NM_000017.4	ENSP00000242592.4
ACADS	ENST00000411593.2	c.321T>C	p.Arg107Arg	synonymous_variant	Exon 3 of 10	2		ENSP00000401045.2
ACADS	ENST00000539690.1	n.433T>C		non_coding_transcript_exon_variant	Exon 3 of 3	2
ENSG00000255946	ENST00000724268.1	n.305-6808A>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79289 AN: 152088 Hom.: 21272 Cov.: 35

Gnomad AFR AF: 0.631

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.542

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.532

GnomAD2 exomes AF: 0.521 AC: 113095 AN: 217102 AF XY: 0.521

Gnomad AFR exome AF: 0.633

Gnomad AMR exome AF: 0.622

Gnomad ASJ exome AF: 0.479

Gnomad EAS exome AF: 0.534

Gnomad FIN exome AF: 0.460

Gnomad NFE exome AF: 0.449

Gnomad OTH exome AF: 0.527

GnomAD4 exome AF: 0.468 AC: 673853 AN: 1441324 Hom.: 160839 Cov.: 67 AF XY: 0.473 AC XY: 337841 AN XY: 714954

African (AFR) AF: 0.639 AC: 21182 AN: 33148

American (AMR) AF: 0.614 AC: 25790 AN: 41988

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 12366 AN: 25670

East Asian (EAS) AF: 0.485 AC: 18862 AN: 38920

South Asian (SAS) AF: 0.646 AC: 53746 AN: 83242

European-Finnish (FIN) AF: 0.455 AC: 23446 AN: 51486

Middle Eastern (MID) AF: 0.617 AC: 3545 AN: 5742

European-Non Finnish (NFE) AF: 0.441 AC: 485328 AN: 1101522

Other (OTH) AF: 0.496 AC: 29588 AN: 59606

GnomAD4 genome AF: 0.521 AC: 79361 AN: 152206 Hom.: 21302 Cov.: 35 AF XY: 0.529 AC XY: 39353 AN XY: 74390

African (AFR) AF: 0.631 AC: 26210 AN: 41550

American (AMR) AF: 0.568 AC: 8694 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1661 AN: 3472

East Asian (EAS) AF: 0.541 AC: 2795 AN: 5164

South Asian (SAS) AF: 0.639 AC: 3086 AN: 4828

European-Finnish (FIN) AF: 0.461 AC: 4890 AN: 10598

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.446 AC: 30323 AN: 67982

Other (OTH) AF: 0.535 AC: 1130 AN: 2112

Alfa AF: 0.482 Hom.: 27681

Bravo AF: 0.531

Asia WGS AF: 0.618 AC: 2148 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase Benign:4

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 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 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 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. -

Jan 05, 2017

Eurofins Ntd Llc (ga)

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	-0.64
CADD	Benign	4.9
DANN	Benign	0.62
PhyloP100		-0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

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: rs3914; hg19: chr12-121174899; COSMIC: COSV54370098; COSMIC: COSV54370098;