12-120725830-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_000017.4(ACADS):​c.-56C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00056 in 1,518,434 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00059 (7 hom.)
• Consequence: ACADS NM_000017.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BS2: High Homozygotes in GnomAdExome4 at 7 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_000008.1	P16219
	ACADS	NM_000017.4	MANE Select	c.-56C>T		5_prime_UTR	Exon 1 of 10	NP_000008.1	P16219
	ACADS	NM_001302554.2		c.-56C>T		5_prime_UTR_premature_start_codon_gain	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>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000242592.4	P16219
	ACADS	ENST00000242592.9	TSL:1 MANE Select	c.-56C>T		5_prime_UTR	Exon 1 of 10	ENSP00000242592.4	P16219
	ACADS	ENST00000946559.1		c.-56C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000616618.1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152080 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00934

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000590 AC: 806 AN: 1366240 Hom.: 7 Cov.: 29 AF XY: 0.000847 AC XY: 572 AN XY: 674964

African (AFR) AF: 0.0000348 AC: 1 AN: 28746

American (AMR) AF: 0.0000286 AC: 1 AN: 34970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24556

East Asian (EAS) AF: 0.0000294 AC: 1 AN: 34030

South Asian (SAS) AF: 0.00984 AC: 768 AN: 78028

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4700

European-Non Finnish (NFE) AF: 0.00000561 AC: 6 AN: 1069638

Other (OTH) AF: 0.000508 AC: 29 AN: 57122

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152194 Hom.: 1 Cov.: 31 AF XY: 0.000484 AC XY: 36 AN XY: 74392

African (AFR) AF: 0.00 AC: 0 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00934 AC: 45 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: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Deficiency of butyryl-CoA dehydrogenase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.90
PhyloP100		0.82
PromoterAI		-0.55	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs567626964;

hg19: chr12-121163633;