10-123034378-G-GT

Variant names:

• chr10-123034378-G-GT
• rs1850369146
• NM_001609.4:c.68dupT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001609.4(ACADSB):​c.68dupT​(p.Leu23PhefsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,152 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: ACADSB NM_001609.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.0130

Genes affected

ACADSB (HGNC:91): (acyl-CoA dehydrogenase short/branched chain) Short/branched chain acyl-CoA dehydrogenase(ACADSB) is a member of the acyl-CoA dehydrogenase family of enzymes that catalyze the dehydrogenation of acyl-CoA derivatives in the metabolism of fatty acids or branch chained amino acids. Substrate specificity is the primary characteristic used to define members of this gene family. The ACADSB gene product has the greatest activity towards the short branched chain acyl-CoA derivative, (S)-2-methylbutyryl-CoA, but also reacts significantly with other 2-methyl branched chain substrates and with short straight chain acyl-CoAs. The cDNA encodes for a mitochondrial precursor protein which is cleaved upon mitochondrial import and predicted to yield a mature peptide of approximately 43.7-KDa. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-123034378-G-GT is Pathogenic according to our data. Variant chr10-123034378-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3075976.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADSB	NM_001609.4	c.68dupT	p.Leu23PhefsTer25	frameshift_variant	Exon 2 of 11	ENST00000358776.7	NP_001600.1
ACADSB	NM_001330174.3	c.-138dupT		5_prime_UTR_variant	Exon 2 of 10		NP_001317103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADSB	ENST00000358776.7	c.68dupT	p.Leu23PhefsTer25	frameshift_variant	Exon 2 of 11	1	NM_001609.4	ENSP00000357873.3
ACADSB	ENST00000368869	c.-138dupT		5_prime_UTR_variant	Exon 2 of 10	2		ENSP00000357862.4
ACADSB	ENST00000411816.2	n.85dupT		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74322

Gnomad4 AFR AF: 0.0000241

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: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of 2-methylbutyryl-CoA dehydrogenase Pathogenic:1

Jan 08, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu23PhefsX25 variant in ACADSB has not been previously reported in individuals with short/branched chain acyl-CoA dehydrogenase deficiency (SBCAD, also known as 2-methylbutyryl-CoA dehydrogenase deficiency) but has been identified in 0.002% (1/41438) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 23 and leads to a premature termination codon 25 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the ACADSB gene is an established disease mechanism in autosomal recessive SBCAD. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive short/branched chain acyl-CoA dehydrogenase deficiency (SBCAD). ACMG/AMP Criteria applied: PVS1, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1850369146; hg19: chr10-124793894;