chr15-40405828-A-G

Variant names:

• chr15-40405828-A-G
• NM_002225.5:c.1A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_002225.5(IVD):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IVD NM_002225.5 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.06

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 4 pathogenic variants. Next in-frame start position is after 53 codons. Genomic position: 40407648. Lost 0.123 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-40405828-A-G is Pathogenic according to our data. Variant chr15-40405828-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3577092.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IVD	NM_002225.5	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	ENST00000487418.8	NP_002216.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IVD	ENST00000487418.8	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	1	NM_002225.5	ENSP00000418397.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Isovaleryl-CoA dehydrogenase deficiency Pathogenic:1

May 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	21
DANN	Benign	0.97
Eigen	Benign	-0.086
Eigen_PC	Benign	0.0048
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.48	.;T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Uncertain	0.021	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.42	.;N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.013	.;D;D
Sift4G	Benign	0.27	T;T;T
Vest4		0.62, 0.67
MVP		0.86
MPC		0.34
ClinPred		0.97	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-40698029;