rs147546456

Variant names:

• chr17-7224575-C-T
• rs147546456
• NM_000018.4:c.1678+23C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-7224575-C-T
• chr17-7224575-C-A
• chr17-7224575-C-G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000018.4(ACADVL):​c.1678+23C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,608,400 control chromosomes in the GnomAD database, including 2 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 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (1 hom.)
• Consequence: ACADVL NM_000018.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 0.716
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 17-7224575-C-T is Benign according to our data. Variant chr17-7224575-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 541727.

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.1678+23C>T		intron	N/A	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.1747+23C>T		intron	N/A	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.1612+23C>T		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.1678+23C>T		intron	N/A	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.1612+23C>T		intron	N/A	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.1747+23C>T		intron	N/A	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 247 AN: 152134 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00262

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00160 AC: 389 AN: 243308 AF XY: 0.00165

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00551

Gnomad NFE exome AF: 0.00236

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00181 AC: 2640 AN: 1456148 Hom.: 1 Cov.: 42 AF XY: 0.00176 AC XY: 1277 AN XY: 724260

African (AFR) AF: 0.000299 AC: 10 AN: 33464

American (AMR) AF: 0.000247 AC: 11 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86066

European-Finnish (FIN) AF: 0.00487 AC: 238 AN: 48918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5394

European-Non Finnish (NFE) AF: 0.00201 AC: 2235 AN: 1111604

Other (OTH) AF: 0.00199 AC: 120 AN: 60302

GnomAD4 genome AF: 0.00162 AC: 247 AN: 152252 Hom.: 1 Cov.: 32 AF XY: 0.00159 AC XY: 118 AN XY: 74444

African (AFR) AF: 0.000265 AC: 11 AN: 41550

American (AMR) AF: 0.000392 AC: 6 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00262 AC: 178 AN: 67994

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00255 Hom.: 0

Bravo AF: 0.00100

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.9
DANN	Benign	0.80
PhyloP100		0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=21/79	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147546456; hg19: chr17-7127894;