17-7224243-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000018.4(ACADVL):​c.1532G>C​(p.Arg511Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,474 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense, splice_region

Scores

7
10
2
Splicing: ADA: 1.000
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.74
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACADVLNM_000018.4 linkc.1532G>C p.Arg511Pro missense_variant, splice_region_variant Exon 15 of 20 ENST00000356839.10 NP_000009.1 P49748-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACADVLENST00000356839.10 linkc.1532G>C p.Arg511Pro missense_variant, splice_region_variant Exon 15 of 20 1 NM_000018.4 ENSP00000349297.5 P49748-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461474
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727060
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Uncertain:1
Aug 30, 2017
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
36
DANN
Benign
0.86
DEOGEN2
Uncertain
0.71
.;D;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Pathogenic
0.49
D
MetaRNN
Uncertain
0.67
D;D;D
MetaSVM
Uncertain
0.60
D
MutationAssessor
Uncertain
2.8
.;M;.
PrimateAI
Uncertain
0.55
T
PROVEAN
Pathogenic
-5.9
D;.;D
REVEL
Pathogenic
0.71
Sift
Uncertain
0.010
D;.;D
Sift4G
Uncertain
0.011
D;D;D
Polyphen
1.0, 0.99
.;D;D
Vest4
0.53
MutPred
0.42
.;Loss of MoRF binding (P = 0.0012);.;
MVP
0.97
MPC
0.91
ClinPred
0.99
D
GERP RS
4.7
Varity_R
0.91
gMVP
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.98
SpliceAI score (max)
0.57
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.57
Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200771970; hg19: chr17-7127562; API