12-120737721-T-C

Variant names:

• chr12-120737721-T-C
• rs2014355
• NM_000017.4:c.473-116T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000017.4(ACADS):​c.473-116T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,468,580 control chromosomes in the GnomAD database, including 49,942 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4334 hom., cov: 33)
  • Exomes 𝑓: 0.26 (45608 hom.)
• Consequence: ACADS NM_000017.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.966
• Publications: 55 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-120737721-T-C is Benign according to our data. Variant chr12-120737721-T-C is described in ClinVar as Benign. ClinVar VariationId is 676089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000017.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADS	NM_000017.4	MANE Select	c.473-116T>C		intron	N/A	NP_000008.1
	ACADS	NM_001302554.2		c.472+254T>C		intron	N/A	NP_001289483.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADS	ENST00000242592.9	TSL:1 MANE Select	c.473-116T>C		intron	N/A	ENSP00000242592.4
	ACADS	ENST00000539690.1	TSL:2	n.1058T>C		non_coding_transcript_exon	Exon 3 of 3
	ACADS	ENST00000411593.2	TSL:2	c.472+254T>C		intron	N/A	ENSP00000401045.2

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33169 AN: 152016 Hom.: 4328 Cov.: 33

Gnomad AFR AF: 0.0901

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.250

GnomAD4 exome AF: 0.259 AC: 340472 AN: 1316446 Hom.: 45608 Cov.: 20 AF XY: 0.260 AC XY: 170142 AN XY: 653314

African (AFR) AF: 0.0834 AC: 2561 AN: 30720

American (AMR) AF: 0.362 AC: 13588 AN: 37524

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 7764 AN: 22840

East Asian (EAS) AF: 0.119 AC: 4547 AN: 38080

South Asian (SAS) AF: 0.293 AC: 22374 AN: 76260

European-Finnish (FIN) AF: 0.266 AC: 11765 AN: 44214

Middle Eastern (MID) AF: 0.363 AC: 1577 AN: 4346

European-Non Finnish (NFE) AF: 0.260 AC: 261667 AN: 1007578

Other (OTH) AF: 0.267 AC: 14629 AN: 54884

GnomAD4 genome AF: 0.218 AC: 33177 AN: 152134 Hom.: 4334 Cov.: 33 AF XY: 0.225 AC XY: 16728 AN XY: 74370

African (AFR) AF: 0.0898 AC: 3727 AN: 41524

American (AMR) AF: 0.314 AC: 4809 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1149 AN: 3470

East Asian (EAS) AF: 0.123 AC: 636 AN: 5164

South Asian (SAS) AF: 0.277 AC: 1336 AN: 4822

European-Finnish (FIN) AF: 0.270 AC: 2861 AN: 10592

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.261 AC: 17752 AN: 67950

Other (OTH) AF: 0.258 AC: 544 AN: 2112

Alfa AF: 0.247 Hom.: 15301

Bravo AF: 0.215

Asia WGS AF: 0.238 AC: 824 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 14, 2018

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.70
DANN	Benign	0.71
PhyloP100		-0.97
Mutation Taster		=100/0	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: rs2014355; hg19: chr12-121175524; COSMIC: COSV54369369; COSMIC: COSV54369369;