chr15-40405844-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002225.5(IVD):​c.17G>A​(p.Arg6Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

IVD
NM_002225.5 missense

Scores

5
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 2.10
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.166094).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IVDNM_002225.5 linkuse as main transcriptc.17G>A p.Arg6Gln missense_variant 1/12 ENST00000487418.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IVDENST00000487418.8 linkuse as main transcriptc.17G>A p.Arg6Gln missense_variant 1/121 NM_002225.5 P4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249106
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135204
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000548
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1459824
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
725904
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:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Isovaleryl-CoA dehydrogenase deficiency Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Feb 22, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeSep 07, 2022This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 9 of the IVD protein (p.Arg9Gln). This variant is present in population databases (rs748160492, gnomAD 0.006%). 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: 948558). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
16
DANN
Uncertain
0.99
Eigen
Benign
-0.90
Eigen_PC
Benign
-0.82
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.61
.;T;T
M_CAP
Uncertain
0.17
D
MetaRNN
Benign
0.17
T;T;T
MetaSVM
Uncertain
0.23
D
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-0.67
.;N;N
REVEL
Uncertain
0.31
Sift
Benign
0.26
.;T;T
Sift4G
Benign
0.19
T;T;T
Vest4
0.22, 0.30
MVP
0.56
MPC
0.38
ClinPred
0.11
T
GERP RS
2.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.0
Varity_R
0.034

Splicing

Name
Calibrated prediction
Score
Prediction
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

Publications

LitVar

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

Other links and lift over

dbSNP: rs748160492; hg19: chr15-40698045; API