12-120725888-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_SupportingPM2PP5_Moderate

The NM_000017.4(ACADS):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000658 in 152,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

ACADS
NM_000017.4 start_lost

Scores

6
5
5

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.64
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1
Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 117 CDS bases. Genomic position: 120727096. Lost 0.094 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-120725888-G-A is Pathogenic according to our data. Variant chr12-120725888-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2709405.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACADSNM_000017.4 linkc.3G>A p.Met1? start_lost Exon 1 of 10 ENST00000242592.9 NP_000008.1 P16219E5KSD5
ACADSNM_001302554.2 linkc.3G>A p.Met1? start_lost Exon 1 of 10 NP_001289483.1 P16219E9PE82B4DUH1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACADSENST00000242592.9 linkc.3G>A p.Met1? start_lost Exon 1 of 10 1 NM_000017.4 ENSP00000242592.4 P16219
ACADSENST00000411593.2 linkc.3G>A p.Met1? start_lost Exon 1 of 10 2 ENSP00000401045.2 E9PE82
ACADSENST00000539690.1 linkn.115G>A non_coding_transcript_exon_variant Exon 1 of 3 2

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152028
Hom.:
0
Cov.:
32
show subpopulations
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1401346
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
694182
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152028
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74250
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024This sequence change affects the initiator methionine of the ACADS mRNA. The next in-frame methionine is located at codon 40. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with short-chain acyl-coenzyme A dehydrogenase deficiency (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant disrupts a region of the ACADS protein in which other variant(s) (p.Arg23Trp) have been observed in individuals with ACADS-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.48
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.32
T;T
Eigen
Benign
0.017
Eigen_PC
Benign
-0.028
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Uncertain
0.58
D
PROVEAN
Benign
-0.62
N;N
REVEL
Pathogenic
0.67
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.028
D;D
Polyphen
0.27
B;P
Vest4
0.78
MutPred
0.68
Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);
MVP
0.97
ClinPred
0.99
D
GERP RS
3.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.96
gMVP
0.51

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1883065804; hg19: chr12-121163691; API