15-40407739-T-C

Variant names:

• chr15-40407739-T-C
• rs2289331
• NM_002225.5:c.234+14T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001354600.3(IVD):​c.248T>C​(p.Val83Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.662 in 1,610,246 control chromosomes in the GnomAD database, including 356,328 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V83I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.63 (31248 hom., cov: 32)
  • Exomes 𝑓: 0.67 (325080 hom.)
• Consequence: IVD NM_001354600.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.60
• Publications: 18 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0596012E-6).
• BP6: Variant 15-40407739-T-C is Benign according to our data. Variant chr15-40407739-T-C is described in ClinVar as Benign. ClinVar VariationId is 94053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354600.3. 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.234+14T>C		intron	N/A	NP_002216.3	A0A0A0MT83
	IVD	NM_001354600.3		c.248T>C	p.Val83Ala	missense	Exon 2 of 13	NP_001341529.2
	IVD	NM_001354599.3		c.248T>C	p.Val83Ala	missense	Exon 2 of 12	NP_001341528.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IVD	ENST00000487418.8	TSL:1 MANE Select	c.234+14T>C		intron	N/A	ENSP00000418397.3	A0A0A0MT83
	IVD	ENST00000479013.7	TSL:1	c.145-200T>C		intron	N/A	ENSP00000417990.3	A0A0S2Z4K7
	IVD	ENST00000610693.5	TSL:2	c.248T>C	p.Val83Ala	missense	Exon 2 of 5	ENSP00000479359.2	A0A087WVD3

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96207 AN: 151918 Hom.: 31220 Cov.: 32

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.680

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.825

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.655

Gnomad OTH AF: 0.622

GnomAD2 exomes AF: 0.687 AC: 172791 AN: 251364 AF XY: 0.693

Gnomad AFR exome AF: 0.496

Gnomad AMR exome AF: 0.698

Gnomad ASJ exome AF: 0.677

Gnomad EAS exome AF: 0.812

Gnomad FIN exome AF: 0.808

Gnomad NFE exome AF: 0.654

Gnomad OTH exome AF: 0.669

GnomAD4 exome AF: 0.665 AC: 970065 AN: 1458210 Hom.: 325080 Cov.: 33 AF XY: 0.669 AC XY: 485153 AN XY: 725684

African (AFR) AF: 0.489 AC: 16337 AN: 33396

American (AMR) AF: 0.693 AC: 31001 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 17496 AN: 26114

East Asian (EAS) AF: 0.835 AC: 33141 AN: 39684

South Asian (SAS) AF: 0.750 AC: 64655 AN: 86154

European-Finnish (FIN) AF: 0.807 AC: 43111 AN: 53410

Middle Eastern (MID) AF: 0.635 AC: 3574 AN: 5632

European-Non Finnish (NFE) AF: 0.650 AC: 720997 AN: 1108836

Other (OTH) AF: 0.660 AC: 39753 AN: 60266

GnomAD4 genome AF: 0.633 AC: 96287 AN: 152036 Hom.: 31248 Cov.: 32 AF XY: 0.644 AC XY: 47858 AN XY: 74348

African (AFR) AF: 0.495 AC: 20484 AN: 41366

American (AMR) AF: 0.672 AC: 10270 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 2326 AN: 3472

East Asian (EAS) AF: 0.805 AC: 4170 AN: 5180

South Asian (SAS) AF: 0.750 AC: 3622 AN: 4832

European-Finnish (FIN) AF: 0.825 AC: 8756 AN: 10610

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.655 AC: 44545 AN: 67980

Other (OTH) AF: 0.622 AC: 1309 AN: 2106

Alfa AF: 0.641 Hom.: 16137

Bravo AF: 0.615

TwinsUK AF: 0.654 AC: 2426

ALSPAC AF: 0.652 AC: 2513

ESP6500AA AF: 0.485 AC: 2137

ESP6500EA AF: 0.652 AC: 5609

ExAC AF: 0.683 AC: 82985

Asia WGS AF: 0.725 AC: 2523 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Isovaleryl-CoA dehydrogenase deficiency (5)
-	-	4	not specified (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.2
DANN	Benign	0.31
FATHMM_MKL	Benign	0.020	N
MetaRNN	Benign	0.0000011	T
PhyloP100		-1.6
Sift4G	Benign	0.21	T
GERP RS		-0.19
PromoterAI		0.052	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs2289331; hg19: chr15-40699940;