17-7222022-T-A

Position:

• chr17-7222022-T-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP7 BP4 BA1

This summary comes from the ClinGen Evidence Repository: The NM_000018.4(ACADVL):c.693T>A (p.Ser231=) variant is a synonymous (silent) variant that is not predicted by SpliceAI and NNSplice to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP and PhastCons (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.2061 in the African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BP4 (ACADVL VCEP specifications version 1; approved November 9, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA289257/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.0062 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (9 hom.)
• Consequence: ACADVL NM_000018.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:9
• Conservation: PhyloP100: -2.21

Genes affected

ACADVL (HGNC:92): (acyl-CoA dehydrogenase very long chain) The protein encoded by this gene is targeted to the inner mitochondrial membrane where it catalyzes the first step of the mitochondrial fatty acid beta-oxidation pathway. This acyl-Coenzyme A dehydrogenase is specific to long-chain and very-long-chain fatty acids. A deficiency in this gene product reduces myocardial fatty acid beta-oxidation and is associated with cardiomyopathy. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4	c.693T>A	p.Ser231=	synonymous_variant	8/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.693T>A	p.Ser231=	synonymous_variant	8/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes AF: 0.00622 AC: 946 AN: 152148 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00194 AC: 488 AN: 251456 Hom.: 5 AF XY: 0.00148 AC XY: 201 AN XY: 135918

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000757 AC: 1106 AN: 1461880 Hom.: 9 Cov.: 32 AF XY: 0.000701 AC XY: 510 AN XY: 727244

Gnomad4 AFR exome AF: 0.0198

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000917

Gnomad4 NFE exome AF: 0.000153

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00622 AC: 947 AN: 152266 Hom.: 18 Cov.: 32 AF XY: 0.00594 AC XY: 442 AN XY: 74454

Gnomad4 AFR AF: 0.0202

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.000558 Hom.: 0

Bravo AF: 0.00677

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Mar 26, 2024	The NM_000018.4(ACADVL):c.693T>A (p.Ser231=) variant is a synonymous (silent) variant that is not predicted by SpliceAI and NNSplice to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP and PhastCons (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.2061 in the African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BP4 (ACADVL VCEP specifications version 1; approved November 9, 2021). -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 12, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.9
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs77763289; hg19: chr17-7125341;