rs150855952

chr15-40418234-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002225.5(IVD):c.1243G>A(p.Gly415Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: IVD NM_002225.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 10.0

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IVD	NM_002225.5	c.1243G>A	p.Gly415Ser	missense_variant	12/12	ENST00000487418.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IVD	ENST00000487418.8	c.1243G>A	p.Gly415Ser	missense_variant	12/12	1	NM_002225.5	P4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251482 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135918

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461858 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74324

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Isovaleryl-CoA dehydrogenase deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 10, 2022	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 418 of the IVD protein (p.Gly418Ser). This variant is present in population databases (rs150855952, gnomAD 0.01%). This missense change has been observed in individual(s) with a positive newborn screening result for IVD-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 203784). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 22, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Pathogenic	0.92
Sift	Benign	0.048	D;T
Sift4G	Benign	0.16	T;T
Vest4		0.73
MVP		0.98
MPC		1.0
ClinPred		0.87	D
GERP RS		5.2
Varity_R		0.86

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: rs150855952; hg19: chr15-40710433; COSMIC: COSV105071917; COSMIC: COSV105071917;