12-120725887-T-C

Position:

• chr12-120725887-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000017.4(ACADS):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,553,102 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: ACADS NM_000017.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.846

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000017.4 (ACADS) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 552667
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-120725887-T-C is Pathogenic according to our data. Variant chr12-120725887-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2501121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADS	NM_000017.4	c.2T>C	p.Met1?	start_lost	1/10	ENST00000242592.9
ACADS	NM_001302554.2	c.2T>C	p.Met1?	start_lost	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADS	ENST00000242592.9	c.2T>C	p.Met1?	start_lost	1/10	1	NM_000017.4	P1
ACADS	ENST00000411593.2	c.2T>C	p.Met1?	start_lost	1/10	2
ACADS	ENST00000539690.1	n.114T>C		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151964 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000128 AC: 2 AN: 156242 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 86898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000300

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 24 AN: 1401138 Hom.: 0 Cov.: 31 AF XY: 0.0000216 AC XY: 15 AN XY: 694038

Gnomad4 AFR exome AF: 0.0000326

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: 0.0000202

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151964 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74196

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 06, 2023	Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 2501121). Disruption of the initiator codon has been observed in individual(s) with short-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 18523805; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects the initiator methionine of the ACADS mRNA. The next in-frame methionine is located at codon 40. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 15, 2023	Variant summary: ACADS c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of two in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 156242 control chromosomes. c.2T>C has been reported in the literature in individuals affected with Deficiency Of Butyryl-CoA Dehydrogenase. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that no detectable SCAD protein in the two patients carrying this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. However, c.1A>G (p.Met1Val) was reported in ClinVar with conflicting interpretations of pathogenicity (likely pathogenic n=2, VUS n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.33	T;T
Eigen	Benign	-0.015
Eigen_PC	Benign	-0.089
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.57	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.74	N;N
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.46	P;P
Vest4		0.82
MutPred		0.90		Gain of glycosylation at M1 (P = 0.0213);Gain of glycosylation at M1 (P = 0.0213);
MVP		0.99
ClinPred		0.96	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.93
gMVP		0.67

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

Other links and lift over

dbSNP: rs990322697; hg19: chr12-121163690;