2-210203385-GGT-G

Variant names:

• chr2-210203385-GGT-G
• rs549315531
• NM_001608.4:c.928_929delAC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001608.4(ACADL):​c.928_929delAC​(p.Thr310GlnfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00678 in 1,611,572 control chromosomes in the GnomAD database, including 52 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0051 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (50 hom.)
• Consequence: ACADL NM_001608.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.48

Genes affected

ACADL (HGNC:88): (acyl-CoA dehydrogenase long chain) The protein encoded by this gene belongs to the acyl-CoA dehydrogenase family, which is a family of mitochondrial flavoenzymes involved in fatty acid and branched chain amino-acid metabolism. This protein is one of the four enzymes that catalyze the initial step of mitochondrial beta-oxidation of straight-chain fatty acid. Defects in this gene are the cause of long-chain acyl-CoA dehydrogenase (LCAD) deficiency, leading to nonketotic hypoglycemia. [provided by RefSeq, Jul 2008]

ENSG00000279317 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADL	NM_001608.4	c.928_929delAC	p.Thr310GlnfsTer5	frameshift_variant	Exon 8 of 11	ENST00000233710.4	NP_001599.1
ACADL	XM_005246517.5	c.865_866delAC	p.Thr289GlnfsTer5	frameshift_variant	Exon 8 of 11		XP_005246574.1
ACADL	XM_047444103.1	c.505_506delAC	p.Thr169GlnfsTer5	frameshift_variant	Exon 8 of 11		XP_047300059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADL	ENST00000233710.4	c.928_929delAC	p.Thr310GlnfsTer5	frameshift_variant	Exon 8 of 11	1	NM_001608.4	ENSP00000233710.3
ACADL	ENST00000652584.1	n.1156_1157delAC		non_coding_transcript_exon_variant	Exon 8 of 11
ENSG00000279317	ENST00000412065.1	n.313-15086_313-15085delGT		intron_variant	Intron 1 of 2	4
ENSG00000279317	ENST00000639259.2	n.280-26897_280-26896delGT		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.00513 AC: 780 AN: 152074 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00492

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00745

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00695 AC: 10149 AN: 1459380 Hom.: 50 AF XY: 0.00668 AC XY: 4850 AN XY: 726004

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00249

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00382

Gnomad4 FIN exome AF: 0.0104

Gnomad4 NFE exome AF: 0.00783

Gnomad4 OTH exome AF: 0.00620

GnomAD4 genome AF: 0.00513 AC: 780 AN: 152192 Hom.: 2 Cov.: 32 AF XY: 0.00513 AC XY: 382 AN XY: 74406

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00491

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0111

Gnomad4 NFE AF: 0.00745

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00508 Hom.: 1

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Nov 01, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACADL c.928_933delinsCATGAATGTTATGTTT; p.Thr310fs variant, to our knowledge, has not been reported in the medical literature or gene specific databases. Due to the complex nature of this variant, next generation sequencing pipelines do not accurately call this variant across multiple platforms. Due to the imprecise nature of the annotation, population frequency estimates may not be accurate. However, by examining raw read data in the Genome Aggregation Database linked to a different variant (listed in dbSNP under rs549315531), it appears that the c.928_933delinsCATGAATGTTATGTTT variant is indeed present in the Finnish population with an allele frequency of 1.1% (37/3,486 alleles), suggesting that this variant is common. This variant introduces a frameshift in exon 8 (of 11) and is expected to result in a truncated or absent protein product. While this variant is predicted to be damaging to the ACADL enzyme, as a clear genotype/phenotype disease association has yet to be firmly established for ACADL, based on the available information, the clinical significance of this variant is uncertain. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

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: rs549315531; hg19: chr2-211068109; COSMIC: COSV52052259;