17-7222150-C-T

Variant names:

• chr17-7222150-C-T
• rs374911841
• NM_000018.4:c.753-27C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS1

This summary comes from the ClinGen Evidence Repository: The c.753-27C>T variant in ACADVL is an intronic variant which occurs in intron 8. The highest population minor allele frequency in gnomAD v4.1 is 0.0036 in non-Finnish European population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.0035) for BS1, and therefore meets this criterion (BS1). The computational splicing predictor SpliceAI gives a score of 0.14 for acceptor loss suggesting that the variant has no impact on splicing (BP4). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID:27246109). 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: BS1, BP4. (ACADVL VCEP specifications version 1; approved November 9, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8337840/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (7 hom.)
• Consequence: ACADVL NM_000018.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -3.25
• Publications: 0 publications found

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]

ACADVL Gene-Disease associations (from GenCC):

• very long chain acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000018.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	NM_000018.4	MANE Select	c.753-27C>T		intron	N/A	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.822-27C>T		intron	N/A	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.687-27C>T		intron	N/A	NP_001029031.1	P49748-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.753-27C>T		intron	N/A	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.687-27C>T		intron	N/A	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000945307.1		c.501C>T	p.His167His	synonymous	Exon 7 of 18	ENSP00000615366.1

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 252 AN: 152218 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00168 AC: 422 AN: 251488 AF XY: 0.00163

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00301

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00304 AC: 4442 AN: 1461866 Hom.: 7 Cov.: 32 AF XY: 0.00292 AC XY: 2126 AN XY: 727238

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.000626 AC: 28 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00134 AC: 116 AN: 86256

European-Finnish (FIN) AF: 0.000936 AC: 50 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00367 AC: 4080 AN: 1112002

Other (OTH) AF: 0.00250 AC: 151 AN: 60396

GnomAD4 genome AF: 0.00166 AC: 253 AN: 152336 Hom.: 1 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74492

African (AFR) AF: 0.000481 AC: 20 AN: 41566

American (AMR) AF: 0.000654 AC: 10 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4832

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00303 AC: 206 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000510 Hom.: 0

Bravo AF: 0.00180

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Very long chain acyl-CoA dehydrogenase deficiency (3)
-	-	1	ACADVL-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0040
DANN	Benign	0.62
PhyloP100		-3.3
BranchPoint Hunter		0.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs374911841; hg19: chr17-7125469;