NM_001354601.3:c.1138+8741G>A

Variant names:

• chr15-40425103-G-A
• rs2034650
• NM_001354601.3:c.1138+8741G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001354601.3(IVD):​c.1138+8741G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 152,100 control chromosomes in the GnomAD database, including 18,428 homozygotes. 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: 𝑓 0.47 (18428 hom., cov: 32)
• Consequence: IVD NM_001354601.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.233

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IVD	NM_001354601.3	c.1138+8741G>A		intron_variant	Intron 11 of 11		NP_001341530.2
IVD	NM_001354600.3	c.1307+887G>A		intron_variant	Intron 12 of 12		NP_001341529.2
IVD	NM_001354598.3	c.1220+887G>A		intron_variant	Intron 12 of 12		NP_001341527.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IVD	ENST00000473112.6	c.718-8751G>A		intron_variant	Intron 7 of 8	5		ENSP00000417256.2
IVD	ENST00000491554.6	c.617+887G>A		intron_variant	Intron 7 of 7	3		ENSP00000453146.1
IVD	ENST00000481262.6	n.*213+8741G>A		intron_variant	Intron 7 of 7	5		ENSP00000452949.1

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70801 AN: 151982 Hom.: 18420 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.519

Gnomad EAS AF: 0.793

Gnomad SAS AF: 0.646

Gnomad FIN AF: 0.611

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.474

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.466 AC: 70839 AN: 152100 Hom.: 18428 Cov.: 32 AF XY: 0.476 AC XY: 35372 AN XY: 74360

Gnomad4 AFR AF: 0.229

Gnomad4 AMR AF: 0.564

Gnomad4 ASJ AF: 0.519

Gnomad4 EAS AF: 0.793

Gnomad4 SAS AF: 0.647

Gnomad4 FIN AF: 0.611

Gnomad4 NFE AF: 0.523

Gnomad4 OTH AF: 0.475

Alfa AF: 0.511 Hom.: 33199

Bravo AF: 0.452

Asia WGS AF: 0.644 AC: 2239 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.4
DANN	Benign	0.54

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2034650; hg19: chr15-40717302;