chr15-40416285-C-T

Position:

• chr15-40416285-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002225.5(IVD):​c.1066-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,614,200 control chromosomes in the GnomAD database, including 238 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (99 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (139 hom.)
• Consequence: IVD NM_002225.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003376
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.759

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=-0.72).
• BP6: Variant 15-40416285-C-T is Benign according to our data. Variant chr15-40416285-C-T is described in ClinVar as [Benign]. Clinvar id is 315803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40416285-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IVD	NM_002225.5	c.1066-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000487418.8	NP_002216.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IVD	ENST00000487418.8	c.1066-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002225.5	ENSP00000418397	P4

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3122 AN: 152246 Hom.: 99 Cov.: 32

Gnomad AFR AF: 0.0669

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0401

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00763 AC: 1918 AN: 251456 Hom.: 60 AF XY: 0.00605 AC XY: 822 AN XY: 135900

Gnomad AFR exome AF: 0.0667

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0390

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00295 AC: 4315 AN: 1461838 Hom.: 139 Cov.: 33 AF XY: 0.00269 AC XY: 1957 AN XY: 727222

Gnomad4 AFR exome AF: 0.0706

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0362

Gnomad4 SAS exome AF: 0.000603

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000639

Gnomad4 OTH exome AF: 0.00439

GnomAD4 genome AF: 0.0205 AC: 3120 AN: 152362 Hom.: 99 Cov.: 32 AF XY: 0.0198 AC XY: 1476 AN XY: 74508

Gnomad4 AFR AF: 0.0667

Gnomad4 AMR AF: 0.00594

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0400

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00863 Hom.: 25

Bravo AF: 0.0233

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Isovaleryl-CoA dehydrogenase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 09, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2015

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	-0.72
CADD	Benign	2.5
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs115077254; hg19: chr15-40708484;