rs2230180

Variant names:

• chr17-7224388-G-A
• rs2230180
• NM_000018.4:c.1600G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000018.4(ACADVL):​c.1600G>A​(p.Glu534Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,613,754 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0084 (26 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (16 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 1.49
• Publications: 11 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: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000018.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.007086098).
• BP6: Variant 17-7224388-G-A is Benign according to our data. Variant chr17-7224388-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 21018.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0084 (1279/152222) while in subpopulation AFR AF = 0.0291 (1209/41518). AF 95% confidence interval is 0.0278. There are 26 homozygotes in GnomAd4. There are 583 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

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.1600G>A	p.Glu534Lys	missense	Exon 16 of 20	NP_000009.1
	ACADVL	NM_001270447.2		c.1669G>A	p.Glu557Lys	missense	Exon 17 of 21	NP_001257376.1
	ACADVL	NM_001033859.3		c.1534G>A	p.Glu512Lys	missense	Exon 15 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.1600G>A	p.Glu534Lys	missense	Exon 16 of 20	ENSP00000349297.5
	ACADVL	ENST00000350303.9	TSL:1	c.1534G>A	p.Glu512Lys	missense	Exon 15 of 19	ENSP00000344152.5
	ACADVL	ENST00000543245.6	TSL:2	c.1669G>A	p.Glu557Lys	missense	Exon 17 of 21	ENSP00000438689.2

Frequencies

GnomAD3 genomes AF: 0.00839 AC: 1276 AN: 152104 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00204 AC: 510 AN: 250038 AF XY: 0.00159

Gnomad AFR exome AF: 0.0282

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.000766 AC: 1119 AN: 1461532 Hom.: 16 Cov.: 33 AF XY: 0.000619 AC XY: 450 AN XY: 727066

African (AFR) AF: 0.0276 AC: 924 AN: 33474

American (AMR) AF: 0.00148 AC: 66 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111884

Other (OTH) AF: 0.00176 AC: 106 AN: 60376

GnomAD4 genome AF: 0.00840 AC: 1279 AN: 152222 Hom.: 26 Cov.: 32 AF XY: 0.00783 AC XY: 583 AN XY: 74442

African (AFR) AF: 0.0291 AC: 1209 AN: 41518

American (AMR) AF: 0.00333 AC: 51 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68002

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00330 Hom.: 7

Bravo AF: 0.00938

ESP6500AA AF: 0.0302 AC: 133

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00257 AC: 312

Asia WGS AF: 0.00173 AC: 6 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	Very long chain acyl-CoA dehydrogenase deficiency (7)
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.29	N
PhyloP100		1.5
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.28
Sift	Benign	0.87	T
Sift4G	Benign	0.83	T
Polyphen		0.013	B
Vest4		0.76
MVP		0.74
MPC		0.22
ClinPred		0.0025	T
GERP RS		0.64
Varity_R		0.20
gMVP		0.55
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs2230180; hg19: chr17-7127707;