NM_000018.4:c.1844G>A

Variant names:

• chr17-7224973-G-A
• rs148584617
• NM_000018.4:c.1844G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000018.4(ACADVL):​c.1844G>A​(p.Arg615Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,614,080 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (20 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:7 B:12
• Conservation: PhyloP100: 0.0450
• Publications: 18 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 -18 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000018.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0066580176).
• BP6: Variant 17-7224973-G-A is Benign according to our data. Variant chr17-7224973-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 195448.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00292 (4264/1461790) while in subpopulation MID AF = 0.0133 (77/5768). AF 95% confidence interval is 0.0109. There are 20 homozygotes in GnomAdExome4. There are 2165 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1844G>A	p.Arg615Gln	missense	Exon 20 of 20	NP_000009.1
	ACADVL	NM_001270447.2		c.1913G>A	p.Arg638Gln	missense	Exon 21 of 21	NP_001257376.1
	ACADVL	NM_001033859.3		c.1778G>A	p.Arg593Gln	missense	Exon 19 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.1844G>A	p.Arg615Gln	missense	Exon 20 of 20	ENSP00000349297.5
	ACADVL	ENST00000350303.9	TSL:1	c.1778G>A	p.Arg593Gln	missense	Exon 19 of 19	ENSP00000344152.5
	ACADVL	ENST00000543245.6	TSL:2	c.1913G>A	p.Arg638Gln	missense	Exon 21 of 21	ENSP00000438689.2

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 371 AN: 152172 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00281 AC: 706 AN: 251176 AF XY: 0.00297

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00378

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00292 AC: 4264 AN: 1461790 Hom.: 20 Cov.: 35 AF XY: 0.00298 AC XY: 2165 AN XY: 727208

African (AFR) AF: 0.00134 AC: 45 AN: 33480

American (AMR) AF: 0.00159 AC: 71 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 303 AN: 26136

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

South Asian (SAS) AF: 0.00217 AC: 187 AN: 86256

European-Finnish (FIN) AF: 0.000263 AC: 14 AN: 53326

Middle Eastern (MID) AF: 0.0133 AC: 77 AN: 5768

European-Non Finnish (NFE) AF: 0.00304 AC: 3381 AN: 1112008

Other (OTH) AF: 0.00308 AC: 186 AN: 60394

GnomAD4 genome AF: 0.00244 AC: 372 AN: 152290 Hom.: 2 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74464

African (AFR) AF: 0.000963 AC: 40 AN: 41558

American (AMR) AF: 0.00399 AC: 61 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 33 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4832

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00312 AC: 212 AN: 68016

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00360 Hom.: 7

Bravo AF: 0.00271

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00284 AC: 345

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00528

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	4	5	Very long chain acyl-CoA dehydrogenase deficiency (10)
-	3	5	not provided (8)
-	-	1	ACADVL-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.51	N
PhyloP100		0.045
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.63	N
REVEL	Uncertain	0.40
Sift	Benign	0.49	T
Sift4G	Benign	0.48	T
Polyphen		0.033	B
Vest4		0.66
MVP		0.63
MPC		0.22
ClinPred		0.0040	T
GERP RS		0.89
Varity_R		0.11
gMVP		0.58
Mutation Taster		=94/6	disease causing (ClinVar)

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: rs148584617; hg19: chr17-7128292; COSMIC: COSV106081352; COSMIC: COSV106081352;