rs566691073
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_002225.5(IVD):c.-8T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000683 in 1,611,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
IVD
NM_002225.5 5_prime_UTR
NM_002225.5 5_prime_UTR
Scores
3
2
6
Clinical Significance
Conservation
PhyloP100: -1.61
Genes affected
IVD (HGNC:6186): (isovaleryl-CoA dehydrogenase) Isovaleryl-CoA dehydrogenase (IVD) is a mitochondrial matrix enzyme that catalyzes the third step in leucine catabolism. The genetic deficiency of IVD results in an accumulation of isovaleric acid, which is toxic to the central nervous system and leads to isovaleric acidemia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.938
PP5
?
Variant 15-40405820-T-C is Pathogenic according to our data. Variant chr15-40405820-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551816.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IVD | NM_002225.5 | c.-8T>C | 5_prime_UTR_variant | 1/12 | ENST00000487418.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IVD | ENST00000487418.8 | c.-8T>C | 5_prime_UTR_variant | 1/12 | 1 | NM_002225.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152272Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249708Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135390
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GnomAD4 exome AF: 0.00000617 AC: 9AN: 1459080Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5AN XY: 725330
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152390Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74526
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Isovaleryl-CoA dehydrogenase deficiency Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 08, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2022 | This sequence change affects the initiator methionine of the IVD mRNA. The next in-frame methionine is located at codon 4. This variant is present in population databases (rs566691073, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with IVD-related conditions. ClinVar contains an entry for this variant (Variation ID: 551816). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
N;N;N
Sift4G
Uncertain
D;D;D
Vest4
0.11, 0.11
MutPred
Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at