Variant 2-210203385-GGT-G details in Genebe, Genetics Data Aggregator

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.Thr310fs) 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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.48

Variant links:

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]

ACADL links:

ENSG00000279317 (HGNC:):

ENSG00000279317 links:

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ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
ACADL	NM_001608.4 link	c.928_929delAC	p.Thr310fs	frameshift_variant	8/11	ENST00000233710.4	NP_001599.1	P28330
ACADL	XM_005246517.5 link	c.865_866delAC	p.Thr289fs	frameshift_variant	8/11		XP_005246574.1
ACADL	XM_047444103.1 link	c.505_506delAC	p.Thr169fs	frameshift_variant	8/11		XP_047300059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ACADL	ENST00000233710.4 link	c.928_929delAC	p.Thr310fs	frameshift_variant	8/11	1	NM_001608.4	ENSP00000233710.3	P28330
ACADL	ENST00000652584.1 link	n.1156_1157delAC		non_coding_transcript_exon_variant	8/11
ENSG00000279317	ENST00000412065.1 link	n.313-15086_313-15085delGT		intron_variant		4
ENSG00000279317	ENST00000639259.2 link	n.280-26897_280-26896delGT		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00513

AC:

780

AN:

152074

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00668

AC XY:

4850

AN XY:

726004

show subpopulations

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.:

Cov.:

AF XY:

0.00513

AC XY:

382

AN XY:

74406

show subpopulations

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.:

Asia WGS

AF:

0.00115

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over