15-40407823-C-T

Position:

• chr15-40407823-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.234+98C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 1,431,454 control chromosomes in the GnomAD database, including 132,847 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (12341 hom., cov: 31)
  • Exomes 𝑓: 0.42 (120506 hom.)
• Consequence: IVD NM_002225.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0380

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 (BayesDel_noAF=-0.83).
• BP6: Variant 15-40407823-C-T is Benign according to our data. Variant chr15-40407823-C-T is described in ClinVar as [Benign]. Clinvar id is 1258387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IVD	NM_002225.5	c.234+98C>T		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+98C>T		intron_variant		1	NM_002225.5	ENSP00000418397.3

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58120 AN: 151850 Hom.: 12334 Cov.: 31

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.769

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.390

GnomAD4 exome AF: 0.421 AC: 538606 AN: 1279484 Hom.: 120506 Cov.: 19 AF XY: 0.428 AC XY: 276342 AN XY: 645852

Gnomad4 AFR exome AF: 0.223

Gnomad4 AMR exome AF: 0.548

Gnomad4 ASJ exome AF: 0.431

Gnomad4 EAS exome AF: 0.806

Gnomad4 SAS exome AF: 0.620

Gnomad4 FIN exome AF: 0.452

Gnomad4 NFE exome AF: 0.386

Gnomad4 OTH exome AF: 0.417

GnomAD4 genome AF: 0.383 AC: 58152 AN: 151970 Hom.: 12341 Cov.: 31 AF XY: 0.392 AC XY: 29108 AN XY: 74268

Gnomad4 AFR AF: 0.227

Gnomad4 AMR AF: 0.461

Gnomad4 ASJ AF: 0.428

Gnomad4 EAS AF: 0.769

Gnomad4 SAS AF: 0.623

Gnomad4 FIN AF: 0.460

Gnomad4 NFE AF: 0.397

Gnomad4 OTH AF: 0.393

Alfa AF: 0.402 Hom.: 28107

Bravo AF: 0.376

Asia WGS AF: 0.602 AC: 2093 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.4
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10518693; hg19: chr15-40700022;