rs73383128

chr15-40405915-C-T

Variant summary

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

The NM_002225.5(IVD):c.88C>T(p.His30Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,613,214 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (27 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (18 hom.)
• Consequence: IVD NM_002225.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0130

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 (MetaRNN=0.0039061308).
• BP6: Variant 15-40405915-C-T is Benign according to our data. Variant chr15-40405915-C-T is described in ClinVar as [Benign]. Clinvar id is 258592.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 = 0.00865 (1318/152402) while in subpopulation AFR AF= 0.0303 (1260/41592). AF 95% confidence interval is 0.0289. There are 27 homozygotes in gnomad4. There are 601 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IVD	NM_002225.5	c.88C>T	p.His30Tyr	missense_variant	1/12	ENST00000487418.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IVD	ENST00000487418.8	c.88C>T	p.His30Tyr	missense_variant	1/12	1	NM_002225.5	P4

Frequencies

GnomAD3 genomes AF: 0.00864 AC: 1315 AN: 152284 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.0303

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00215 AC: 531 AN: 247346 Hom.: 11 AF XY: 0.00151 AC XY: 203 AN XY: 134472

Gnomad AFR exome AF: 0.0305

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000451

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000836 AC: 1221 AN: 1460812 Hom.: 18 Cov.: 32 AF XY: 0.000720 AC XY: 523 AN XY: 726720

Gnomad4 AFR exome AF: 0.0292

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000540

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00865 AC: 1318 AN: 152402 Hom.: 27 Cov.: 33 AF XY: 0.00806 AC XY: 601 AN XY: 74532

Gnomad4 AFR AF: 0.0303

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00259 Hom.: 6

Bravo AF: 0.00955

ESP6500AA AF: 0.0291 AC: 128

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00278 AC: 337

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 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. -

Isovaleryl-CoA dehydrogenase deficiency Benign:3

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 26, 2017	- -
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, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	1.6
Dann	Benign	0.92
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.080	N
MetaRNN	Benign	0.0039	T;T;T
MetaSVM	Uncertain	0.0082	D
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.55	T
Sift4G	Benign	1.0	T;T;T
Vest4		0.24, 0.23
MVP		0.38
MPC		0.36
ClinPred		0.0035	T
GERP RS		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.041

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: rs73383128; hg19: chr15-40698116;