NM_000018.4:c.1605+6T>C

Variant names:

• chr17-7224399-T-C
• rs17671352
• NM_000018.4:c.1605+6T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BA1

This summary comes from the ClinGen Evidence Repository: The c.1605+6T>C variant in ACADVL is an intronic variant which occurs in intron 16. The highest population minor allele frequency in gnomAD v2.1.1 is 0.66 in European Finnish population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The results from in silico splicing predictors (SpliceAI) support that this variant does not affect splicing (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation ExpertPanel: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274404/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.57 (25315 hom., cov: 31)
  • Exomes 𝑓: 0.62 (279411 hom.)
• Consequence: ACADVL NM_000018.4 splice_region, intron
• Scores: Splicing: ADA: 0.007159
• Clinical Significance: Benign reviewed by expert panel B:15
• Conservation: PhyloP100: -0.253
• Publications: 22 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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.1605+6T>C		splice_region intron	N/A	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.1674+6T>C		splice_region intron	N/A	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.1539+6T>C		splice_region 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.1605+6T>C		splice_region intron	N/A	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.1539+6T>C		splice_region intron	N/A	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.1674+6T>C		splice_region intron	N/A	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes AF: 0.569 AC: 86437 AN: 151808 Hom.: 25290 Cov.: 31

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.629

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.645

Gnomad FIN AF: 0.675

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.603

GnomAD2 exomes AF: 0.598 AC: 149132 AN: 249274 AF XY: 0.610

Gnomad AFR exome AF: 0.429

Gnomad AMR exome AF: 0.492

Gnomad ASJ exome AF: 0.592

Gnomad EAS exome AF: 0.483

Gnomad FIN exome AF: 0.666

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.613

GnomAD4 exome AF: 0.616 AC: 899884 AN: 1461136 Hom.: 279411 Cov.: 71 AF XY: 0.620 AC XY: 450287 AN XY: 726846

African (AFR) AF: 0.428 AC: 14332 AN: 33476

American (AMR) AF: 0.500 AC: 22339 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.598 AC: 15619 AN: 26134

East Asian (EAS) AF: 0.459 AC: 18208 AN: 39678

South Asian (SAS) AF: 0.659 AC: 56866 AN: 86226

European-Finnish (FIN) AF: 0.659 AC: 35020 AN: 53138

Middle Eastern (MID) AF: 0.692 AC: 3992 AN: 5766

European-Non Finnish (NFE) AF: 0.627 AC: 697229 AN: 1111718

Other (OTH) AF: 0.601 AC: 36279 AN: 60362

GnomAD4 genome AF: 0.569 AC: 86505 AN: 151926 Hom.: 25315 Cov.: 31 AF XY: 0.572 AC XY: 42513 AN XY: 74260

African (AFR) AF: 0.434 AC: 17951 AN: 41402

American (AMR) AF: 0.557 AC: 8506 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 2033 AN: 3468

East Asian (EAS) AF: 0.485 AC: 2501 AN: 5160

South Asian (SAS) AF: 0.647 AC: 3112 AN: 4812

European-Finnish (FIN) AF: 0.675 AC: 7146 AN: 10584

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.636 AC: 43187 AN: 67904

Other (OTH) AF: 0.608 AC: 1280 AN: 2106

Alfa AF: 0.612 Hom.: 9258

Bravo AF: 0.551

Asia WGS AF: 0.578 AC: 2011 AN: 3476

EpiCase AF: 0.654

EpiControl AF: 0.655

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	Very long chain acyl-CoA dehydrogenase deficiency (8)
-	-	6	not specified (6)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.0
DANN	Benign	0.59
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0072
dbscSNV1_RF	Benign	0.062
SpliceAI score (max)		0.040		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: rs17671352; hg19: chr17-7127718; COSMIC: COSV50040336; COSMIC: COSV50040336;