15-40405844-G-T

Variant names:

• chr15-40405844-G-T
• rs748160492
• NM_002225.5:c.17G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001354597.3(IVD):​c.-411G>T 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 0.00000685 in 1,459,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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: 0.0000069 (0 hom.)
• Consequence: IVD NM_001354597.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.10
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• isovaleric acidemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen, G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19142517).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354597.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IVD	NM_002225.5	MANE Select	c.17G>T	p.Arg6Leu	missense	Exon 1 of 12	NP_002216.3	A0A0A0MT83
	IVD	NM_001354597.3		c.-411G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_001341526.1
	IVD	NM_001354601.3		c.17G>T	p.Arg6Leu	missense	Exon 1 of 12	NP_001341530.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IVD	ENST00000487418.8	TSL:1 MANE Select	c.17G>T	p.Arg6Leu	missense	Exon 1 of 12	ENSP00000418397.3	A0A0A0MT83
	IVD	ENST00000479013.7	TSL:1	c.17G>T	p.Arg6Leu	missense	Exon 1 of 11	ENSP00000417990.3	A0A0S2Z4K7
	IVD	ENST00000868500.1		c.17G>T	p.Arg6Leu	missense	Exon 1 of 13	ENSP00000538559.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1459824 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 725904

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5534

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1110788

Other (OTH) AF: 0.00 AC: 0 AN: 60256

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	15
DANN	Benign	0.85
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.81
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.22	D
PhyloP100		2.1
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.43	N
REVEL	Uncertain	0.34
Sift	Benign	0.34	T
Sift4G	Benign	0.12	T
Vest4		0.28
MVP		0.60
MPC		0.40
ClinPred		0.12	T
GERP RS		2.4
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.053
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs748160492; hg19: chr15-40698045;