rs202217537

Variant names:

• chr17-7224083-T-A
• rs202217537
• NM_000018.4:c.1434+14T>A

Your query was ambiguous. Multiple possible variants found:

• chr17-7224083-T-A
• chr17-7224083-T-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000018.4(ACADVL):​c.1434+14T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,613,812 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene ACADVL is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (5 hom.)
• Consequence: ACADVL NM_000018.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: -2.11
• Publications: 2 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-7224083-T-A is Benign according to our data. Variant chr17-7224083-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194313.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.1434+14T>A		intron	N/A	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.1503+14T>A		intron	N/A	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.1368+14T>A		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.1434+14T>A		intron	N/A	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.1368+14T>A		intron	N/A	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.1503+14T>A		intron	N/A	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 151916 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00131 AC: 329 AN: 251302 AF XY: 0.00141

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00225

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00197 AC: 2884 AN: 1461778 Hom.: 5 Cov.: 33 AF XY: 0.00195 AC XY: 1420 AN XY: 727206

African (AFR) AF: 0.000358 AC: 12 AN: 33476

American (AMR) AF: 0.000425 AC: 19 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00122 AC: 105 AN: 86254

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53410

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00239 AC: 2652 AN: 1111926

Other (OTH) AF: 0.00128 AC: 77 AN: 60390

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152034 Hom.: 1 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74320

African (AFR) AF: 0.000169 AC: 7 AN: 41440

American (AMR) AF: 0.000393 AC: 6 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4792

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10598

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

European-Non Finnish (NFE) AF: 0.00212 AC: 144 AN: 67978

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.000503 Hom.: 0

Bravo AF: 0.00117

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Very long chain acyl-CoA dehydrogenase deficiency (4)
-	1	1	not provided (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.0070
DANN	Benign	0.49
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism

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: rs202217537; hg19: chr17-7127402;