NM_002225.5:c.870delG
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_002225.5(IVD):c.870delG(p.Pro291LeufsTer18) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,608 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G290G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
IVD
NM_002225.5 frameshift
NM_002225.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.13
Publications
1 publications found
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]
IVD Gene-Disease associations (from GenCC):
- isovaleric acidemiaInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health, G2P, ClinGen
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-40414968-CG-C is Pathogenic according to our data. Variant chr15-40414968-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 854919.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_002225.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| IVD | NM_002225.5 | MANE Select | c.870delG | p.Pro291LeufsTer18 | frameshift | Exon 8 of 12 | NP_002216.3 | ||
| IVD | NM_001354601.3 | c.870delG | p.Pro291LeufsTer18 | frameshift | Exon 8 of 12 | NP_001341530.2 | |||
| IVD | NM_001354600.3 | c.957delG | p.Pro320LeufsTer18 | frameshift | Exon 8 of 13 | NP_001341529.2 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| IVD | ENST00000487418.8 | TSL:1 MANE Select | c.870delG | p.Pro291LeufsTer18 | frameshift | Exon 8 of 12 | ENSP00000418397.3 | ||
| IVD | ENST00000479013.7 | TSL:1 | c.780delG | p.Pro261LeufsTer18 | frameshift | Exon 7 of 11 | ENSP00000417990.3 | ||
| IVD | ENST00000868500.1 | c.1023delG | p.Pro342LeufsTer18 | frameshift | Exon 9 of 13 | ENSP00000538559.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD2 exomes AF: 0.00 AC: 0AN: 250518 AF XY: 0.00
GnomAD2 exomes
AF:
AC:
0
AN:
250518
AF XY:
Gnomad AFR exome
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Gnomad ASJ exome
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Gnomad FIN exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461608Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727074 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461608
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727074
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33478
American (AMR)
AF:
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39696
South Asian (SAS)
AF:
AC:
0
AN:
86240
European-Finnish (FIN)
AF:
AC:
0
AN:
53234
Middle Eastern (MID)
AF:
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111950
Other (OTH)
AF:
AC:
0
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
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0
1
1
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0.00
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0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
33
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
Isovaleryl-CoA dehydrogenase deficiency (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
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Calibrated prediction
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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
Publications
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