rs373594717

Positions:

• chr15-40405819-A-C
• chr15-40405819-A-G
• chr15-40405819-A-T

Variant summary

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

The NM_002225.5(IVD):​c.-9A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IVD NM_002225.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.48

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 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, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IVD	NM_002225.5	c.-9A>C		5_prime_UTR_premature_start_codon_gain_variant	1/12	ENST00000487418.8	NP_002216.3
IVD	NM_002225.5	c.-9A>C		5_prime_UTR_variant	1/12	ENST00000487418.8	NP_002216.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IVD	ENST00000487418	c.-9A>C		5_prime_UTR_premature_start_codon_gain_variant	1/12	1	NM_002225.5	ENSP00000418397.3
IVD	ENST00000487418	c.-9A>C		5_prime_UTR_variant	1/12	1	NM_002225.5	ENSP00000418397.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249662 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458580 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724960

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	0.031
DANN	Benign	0.43
DEOGEN2	Benign	0.35	.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.060	N
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	-0.19	T
PROVEAN	Benign	-0.060	.;N;N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	.;D;D
Sift4G	Benign	0.25	T;T;T
Vest4		0.13, 0.16
MutPred		0.90		Gain of stability (P = 0.0076);Gain of stability (P = 0.0076);Gain of stability (P = 0.0076);
MVP		0.73
ClinPred		0.18	T
GERP RS		-8.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.71

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: rs373594717; hg19: chr15-40698020;