12-120725907-C-T

Variant names:

• chr12-120725907-C-T
• rs777704501
• NM_000017.4:c.22C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000017.4(ACADS):​c.22C>T​(p.Arg8Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,556,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R8R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ACADS NM_000017.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.513
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.58444 (below the threshold of 3.09). Trascript score misZ: 0.78549 (below the threshold of 3.09). GenCC associations: The gene is linked to short chain acyl-CoA dehydrogenase deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37568527).

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.22C>T	p.Arg8Trp	missense	Exon 1 of 10	NP_000008.1	P16219
	ACADS	NM_001302554.2		c.22C>T	p.Arg8Trp	missense	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.22C>T	p.Arg8Trp	missense	Exon 1 of 10	ENSP00000242592.4	P16219
	ACADS	ENST00000946559.1		c.22C>T	p.Arg8Trp	missense	Exon 1 of 10	ENSP00000616618.1
	ACADS	ENST00000893619.1		c.22C>T	p.Arg8Trp	missense	Exon 1 of 10	ENSP00000563678.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152012 Hom.: 0 Cov.: 32

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: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1404256 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 695902

African (AFR) AF: 0.00 AC: 0 AN: 30634

American (AMR) AF: 0.0000259 AC: 1 AN: 38618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25092

East Asian (EAS) AF: 0.00 AC: 0 AN: 36740

South Asian (SAS) AF: 0.00 AC: 0 AN: 80606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4528

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092568

Other (OTH) AF: 0.00 AC: 0 AN: 58534

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152012 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74242

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	0.0	N
PhyloP100		0.51
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.025	D
Polyphen		0.0020	B
Vest4		0.19
MutPred		0.51		Loss of disorder (P = 0.0016)
MVP		0.93
MPC		0.20
ClinPred		0.58	D
GERP RS		1.1
PromoterAI		0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.15
gMVP		0.61
Mutation Taster		=83/17	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: rs777704501; hg19: chr12-121163710;