12-120725830-C-G

Variant names:

• chr12-120725830-C-G
• rs567626964
• NM_000017.4:c.-56C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000017.4(ACADS):​c.-56C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000716 in 1,518,430 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00055 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (11 hom.)
• Consequence: ACADS NM_000017.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.822
• Publications: 0 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, ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADS	NM_000017.4	MANE Select	c.-56C>G		5_prime_UTR	Exon 1 of 10	NP_000008.1	P16219
	ACADS	NM_001302554.2		c.-56C>G		5_prime_UTR	Exon 1 of 10	NP_001289483.1	E9PE82

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADS	ENST00000242592.9	TSL:1 MANE Select	c.-56C>G		5_prime_UTR	Exon 1 of 10	ENSP00000242592.4	P16219
	ACADS	ENST00000946559.1		c.-56C>G		5_prime_UTR	Exon 1 of 10	ENSP00000616618.1
	ACADS	ENST00000893619.1		c.-56C>G		5_prime_UTR	Exon 1 of 10	ENSP00000563678.1

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152080 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000735 AC: 1004 AN: 1366236 Hom.: 11 Cov.: 29 AF XY: 0.000942 AC XY: 636 AN XY: 674964

African (AFR) AF: 0.000174 AC: 5 AN: 28746

American (AMR) AF: 0.000658 AC: 23 AN: 34970

Ashkenazi Jewish (ASJ) AF: 0.00110 AC: 27 AN: 24556

East Asian (EAS) AF: 0.000500 AC: 17 AN: 34030

South Asian (SAS) AF: 0.00756 AC: 590 AN: 78028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34450

Middle Eastern (MID) AF: 0.00404 AC: 19 AN: 4700

European-Non Finnish (NFE) AF: 0.000243 AC: 260 AN: 1069638

Other (OTH) AF: 0.00110 AC: 63 AN: 57118

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152194 Hom.: 1 Cov.: 31 AF XY: 0.000645 AC XY: 48 AN XY: 74392

African (AFR) AF: 0.000120 AC: 5 AN: 41560

American (AMR) AF: 0.000458 AC: 7 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3464

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5118

South Asian (SAS) AF: 0.00581 AC: 28 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000530 Hom.: 0

Bravo AF: 0.000397

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Deficiency of butyryl-CoA dehydrogenase (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Benign	0.76
PhyloP100		0.82
PromoterAI		-0.58	Under-expression
Mutation Taster		=300/0	polymorphism

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: rs567626964; hg19: chr12-121163633;