rs35501596

Variant names:

• chr17-7223827-G-A
• rs35501596
• NM_000018.4:c.1284G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BP7

This summary comes from the ClinGen Evidence Repository: The c.1284G>A (p.Lys428=) variant (NM_000018.3) is a synonymous (silent) variant that is not predicted by NNSplice, MaxEntScan, and SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (BP4, BP7). The highest population minor allele frequency in gnomAD v4.1 is 0.001 in Non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as likely 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: BP4, BP7 (ACADVL VCEP specifications version 1; approved November 9, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA341515/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (5 hom.)
• Consequence: ACADVL NM_000018.4 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:5
• Conservation: PhyloP100: 0.0390
• Publications: 3 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: G2P, Orphanet, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: 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.1284G>A	p.Lys428Lys	synonymous	Exon 13 of 20	NP_000009.1
	ACADVL	NM_001270447.2		c.1353G>A	p.Lys451Lys	synonymous	Exon 14 of 21	NP_001257376.1
	ACADVL	NM_001033859.3		c.1218G>A	p.Lys406Lys	synonymous	Exon 12 of 19	NP_001029031.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.1284G>A	p.Lys428Lys	synonymous	Exon 13 of 20	ENSP00000349297.5
	ACADVL	ENST00000350303.9	TSL:1	c.1218G>A	p.Lys406Lys	synonymous	Exon 12 of 19	ENSP00000344152.5
	ACADVL	ENST00000543245.6	TSL:2	c.1353G>A	p.Lys451Lys	synonymous	Exon 14 of 21	ENSP00000438689.2

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000744 AC: 187 AN: 251458 AF XY: 0.000846

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000740

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000947 AC: 1384 AN: 1461854 Hom.: 5 Cov.: 33 AF XY: 0.000927 AC XY: 674 AN XY: 727226

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.000648 AC: 29 AN: 44722

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

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

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86252

European-Finnish (FIN) AF: 0.000543 AC: 29 AN: 53390

Middle Eastern (MID) AF: 0.0127 AC: 73 AN: 5768

European-Non Finnish (NFE) AF: 0.00105 AC: 1173 AN: 1112010

Other (OTH) AF: 0.000811 AC: 49 AN: 60396

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000752 AC XY: 56 AN XY: 74476

African (AFR) AF: 0.0000963 AC: 4 AN: 41556

American (AMR) AF: 0.000457 AC: 7 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10608

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000914 Hom.: 1

Bravo AF: 0.000710

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00119

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Very long chain acyl-CoA dehydrogenase deficiency (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.7
DANN	Benign	0.57
PhyloP100		0.039
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35501596; hg19: chr17-7127146;