15-40407739-T-C

Position:

• chr15-40407739-T-C

Variant summary

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

The NM_001354600.3(IVD):​c.248T>C​(p.Val83Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.662 in 1,610,246 control chromosomes in the GnomAD database, including 356,328 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31248 hom., cov: 32)
  • Exomes 𝑓: 0.67 (325080 hom.)
• Consequence: IVD NM_001354600.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.60

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0596012E-6).
• BP6: Variant 15-40407739-T-C is Benign according to our data. Variant chr15-40407739-T-C is described in ClinVar as [Benign]. Clinvar id is 94053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40407739-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IVD	NM_002225.5	c.234+14T>C		intron_variant		ENST00000487418.8	NP_002216.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IVD	ENST00000487418.8	c.234+14T>C		intron_variant		1	NM_002225.5	ENSP00000418397.3

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96207 AN: 151918 Hom.: 31220 Cov.: 32

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.680

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.825

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.655

Gnomad OTH AF: 0.622

GnomAD3 exomes AF: 0.687 AC: 172791 AN: 251364 Hom.: 60207 AF XY: 0.693 AC XY: 94102 AN XY: 135872

Gnomad AFR exome AF: 0.496

Gnomad AMR exome AF: 0.698

Gnomad ASJ exome AF: 0.677

Gnomad EAS exome AF: 0.812

Gnomad SAS exome AF: 0.749

Gnomad FIN exome AF: 0.808

Gnomad NFE exome AF: 0.654

Gnomad OTH exome AF: 0.669

GnomAD4 exome AF: 0.665 AC: 970065 AN: 1458210 Hom.: 325080 Cov.: 33 AF XY: 0.669 AC XY: 485153 AN XY: 725684

Gnomad4 AFR exome AF: 0.489

Gnomad4 AMR exome AF: 0.693

Gnomad4 ASJ exome AF: 0.670

Gnomad4 EAS exome AF: 0.835

Gnomad4 SAS exome AF: 0.750

Gnomad4 FIN exome AF: 0.807

Gnomad4 NFE exome AF: 0.650

Gnomad4 OTH exome AF: 0.660

GnomAD4 genome AF: 0.633 AC: 96287 AN: 152036 Hom.: 31248 Cov.: 32 AF XY: 0.644 AC XY: 47858 AN XY: 74348

Gnomad4 AFR AF: 0.495

Gnomad4 AMR AF: 0.672

Gnomad4 ASJ AF: 0.670

Gnomad4 EAS AF: 0.805

Gnomad4 SAS AF: 0.750

Gnomad4 FIN AF: 0.825

Gnomad4 NFE AF: 0.655

Gnomad4 OTH AF: 0.622

Alfa AF: 0.638 Hom.: 6303

Bravo AF: 0.615

TwinsUK AF: 0.654 AC: 2426

ALSPAC AF: 0.652 AC: 2513

ESP6500AA AF: 0.485 AC: 2137

ESP6500EA AF: 0.652 AC: 5609

ExAC AF: 0.683 AC: 82985

Asia WGS AF: 0.725 AC: 2523 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Isovaleryl-CoA dehydrogenase deficiency Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 12, 2018	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.2
DANN	Benign	0.31
FATHMM_MKL	Benign	0.020	N
MetaRNN	Benign	0.0000011	T
Sift4G	Benign	0.21	T
GERP RS		-0.19

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

Other links and lift over

dbSNP: rs2289331; hg19: chr15-40699940;