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. The variant received -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
• Publications: 38 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), Orphanet, Myriad Women’s Health, G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354601.3. 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_001354601.3		c.1138+8741G>A		intron	N/A	NP_001341530.2
	IVD	NM_001354600.3		c.1307+887G>A		intron	N/A	NP_001341529.2
	IVD	NM_001354598.3		c.1220+887G>A		intron	N/A	NP_001341527.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IVD	ENST00000473112.6	TSL:5	c.718-8751G>A		intron	N/A	ENSP00000417256.2
	IVD	ENST00000491554.6	TSL:3	c.617+887G>A		intron	N/A	ENSP00000453146.1
	IVD	ENST00000481262.6	TSL:5	n.*213+8741G>A		intron	N/A	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

African (AFR) AF: 0.229 AC: 9502 AN: 41504

American (AMR) AF: 0.564 AC: 8620 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 1801 AN: 3472

East Asian (EAS) AF: 0.793 AC: 4110 AN: 5180

South Asian (SAS) AF: 0.647 AC: 3117 AN: 4818

European-Finnish (FIN) AF: 0.611 AC: 6455 AN: 10568

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.523 AC: 35532 AN: 67974

Other (OTH) AF: 0.475 AC: 1005 AN: 2114

Alfa AF: 0.505 Hom.: 79826

Bravo AF: 0.452

Asia WGS AF: 0.644 AC: 2239 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.4
DANN	Benign	0.54
PhyloP100		0.23

Splicing

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

Other links and lift over

dbSNP: rs2034650; hg19: chr15-40717302;