15-40405780-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.447

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]

ACMG classification

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 GnomAd at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IVD	NM_002225.5			upstream_gene_variant		ENST00000487418.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IVD	ENST00000487418.8			upstream_gene_variant		1	NM_002225.5	P4

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1529 AN: 152270 Hom.: 26 Cov.: 33

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

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

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

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

Submissions by phenotype

Isovaleryl-CoA dehydrogenase deficiency Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2016

This 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

Other links and lift over

dbSNP: rs114259808; hg19: chr15-40697981;