chr15-40405780-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000651168.1(IVD):​c.-39G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,599,770 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 25 hom., cov: 33)
Exomes 𝑓: 0.0012 ( 17 hom. )

Consequence

IVD
ENST00000651168.1 5_prime_UTR

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.447
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
Variant 15-40405780-G-A is Benign according to our data. Variant chr15-40405780-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 315796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.01 (1529/152388) while in subpopulation AFR AF= 0.0345 (1436/41592). AF 95% confidence interval is 0.033. There are 25 homozygotes in gnomad4. There are 748 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IVDNM_002225.5 linkuse as main transcript upstream_gene_variant ENST00000487418.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IVDENST00000487418.8 linkuse as main transcript upstream_gene_variant 1 NM_002225.5 P4

Frequencies

GnomAD3 genomes
AF:
0.0100
AC:
1529
AN:
152270
Hom.:
26
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0346
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00307
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0158
Gnomad NFE
AF:
0.000338
Gnomad OTH
AF:
0.00956
GnomAD3 exomes
AF:
0.00280
AC:
687
AN:
245478
Hom.:
8
AF XY:
0.00231
AC XY:
308
AN XY:
133322
show subpopulations
Gnomad AFR exome
AF:
0.0367
Gnomad AMR exome
AF:
0.00242
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000288
Gnomad OTH exome
AF:
0.00135
GnomAD4 exome
AF:
0.00117
AC:
1700
AN:
1447382
Hom.:
17
Cov.:
31
AF XY:
0.00106
AC XY:
762
AN XY:
717240
show subpopulations
Gnomad4 AFR exome
AF:
0.0347
Gnomad4 AMR exome
AF:
0.00237
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000587
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000240
Gnomad4 OTH exome
AF:
0.00245
GnomAD4 genome
AF:
0.0100
AC:
1529
AN:
152388
Hom.:
25
Cov.:
33
AF XY:
0.0100
AC XY:
748
AN XY:
74518
show subpopulations
Gnomad4 AFR
AF:
0.0345
Gnomad4 AMR
AF:
0.00307
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000338
Gnomad4 OTH
AF:
0.00946
Alfa
AF:
0.00452
Hom.:
4
Bravo
AF:
0.0111
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Isovaleryl-CoA dehydrogenase deficiency Benign:2
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMar 24, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
CADD
Benign
9.6
DANN
Benign
0.82

Splicing

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: rs114259808; hg19: chr15-40697981; API