17-7224636-G-C

Variant names:

• chr17-7224636-G-C
• rs113994171
• NM_000018.4:c.1679-6G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000018.4(ACADVL):​c.1679-6G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000091 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACADVL NM_000018.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002455
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.212
• Publications: 5 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).

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.1679-6G>C		splice_region intron	N/A	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.1748-6G>C		splice_region intron	N/A	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.1613-6G>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.1679-6G>C		splice_region intron	N/A	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.1613-6G>C		splice_region intron	N/A	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.1748-6G>C		splice_region intron	N/A	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes AF: 0.000189 AC: 3 AN: 15914 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000351

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000130 AC: 12 AN: 92036 AF XY: 0.0000791

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000340

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000940

Gnomad OTH exome AF: 0.000480

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000907 AC: 35 AN: 385866 Hom.: 0 Cov.: 36 AF XY: 0.000104 AC XY: 20 AN XY: 191564

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000106 AC: 1 AN: 9394

American (AMR) AF: 0.000151 AC: 2 AN: 13244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7446

East Asian (EAS) AF: 0.000509 AC: 3 AN: 5890

South Asian (SAS) AF: 0.000282 AC: 8 AN: 28348

European-Finnish (FIN) AF: 0.000185 AC: 3 AN: 16194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1412

European-Non Finnish (NFE) AF: 0.0000552 AC: 16 AN: 289860

Other (OTH) AF: 0.000142 AC: 2 AN: 14078

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000189 AC: 3 AN: 15914 Hom.: 0 Cov.: 0 AF XY: 0.000366 AC XY: 3 AN XY: 8186

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 3588

American (AMR) AF: 0.00 AC: 0 AN: 1202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 460

East Asian (EAS) AF: 0.00 AC: 0 AN: 584

South Asian (SAS) AF: 0.00 AC: 0 AN: 604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 30

European-Non Finnish (NFE) AF: 0.000351 AC: 3 AN: 8542

Other (OTH) AF: 0.00 AC: 0 AN: 250

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000308 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.3
DANN	Benign	0.47
PhyloP100		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.018
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: rs113994171; hg19: chr17-7127955;