rs139425622

Variant names:

• chr17-7224355-G-A
• rs139425622
• NM_000018.4:c.1567G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-7224355-G-A
• chr17-7224355-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1 BP4

The NM_000018.4(ACADVL):​c.1567G>A​(p.Gly523Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000675 in 1,613,908 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G523G) has been classified as Likely benign. The gene ACADVL is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (1 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:15
• Conservation: PhyloP100: 6.07
• Publications: 8 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

Specifications for ACADVL are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000018.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.37113324).

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.1567G>A	p.Gly523Arg	missense	Exon 16 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.1636G>A	p.Gly546Arg	missense	Exon 17 of 21	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.1501G>A	p.Gly501Arg	missense	Exon 15 of 19	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.1567G>A	p.Gly523Arg	missense	Exon 16 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.1501G>A	p.Gly501Arg	missense	Exon 15 of 19	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.1636G>A	p.Gly546Arg	missense	Exon 17 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000415 AC: 104 AN: 250394 AF XY: 0.000406

Gnomad AFR exome AF: 0.000866

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0000935

Gnomad NFE exome AF: 0.000654

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000680 AC: 994 AN: 1461656 Hom.: 1 Cov.: 33 AF XY: 0.000670 AC XY: 487 AN XY: 727114

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000655 AC: 26 AN: 39694

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86240

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53258

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000783 AC: 871 AN: 1111986

Other (OTH) AF: 0.000662 AC: 40 AN: 60384

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74434

African (AFR) AF: 0.000891 AC: 37 AN: 41536

American (AMR) AF: 0.000131 AC: 2 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000722 Hom.: 0

Bravo AF: 0.000616

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000404 AC: 49

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	9	-	Very long chain acyl-CoA dehydrogenase deficiency (9)
-	3	-	not provided (3)
-	2	-	not specified (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Benign	0.74
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.51
Sift	Benign	0.040	D
Sift4G	Benign	0.10	T
Polyphen		0.99	D
Vest4		0.58
MutPred		0.36		Gain of MoRF binding (P = 0.0147)
MVP		0.95
MPC		0.48
ClinPred		0.11	T
GERP RS		5.4
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.21
gMVP		0.84
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs139425622; hg19: chr17-7127674; COSMIC: COSV104997531; COSMIC: COSV104997531;