rs2289329

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002225.5(IVD):c.688-31T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.416 in 1,595,266 control chromosomes in the GnomAD database, including 146,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.38 ( 12105 hom., cov: 33)

Exomes 𝑓: 0.42 ( 134153 hom. )

Consequence

IVD
NM_002225.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.944

Publications

22 publications found

Variant links:

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: G2P, Myriad Women's Health, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

IVD links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_002225.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 15-40412960-T-C is Benign according to our data. Variant chr15-40412960-T-C is described in ClinVar as Benign. ClinVar VariationId is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002225.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IVD	NM_002225.5	MANE Select	c.688-31T>C	intron	N/A	NP_002216.3	A0A0A0MT83
IVD	NM_001354601.3		c.688-31T>C	intron	N/A	NP_001341530.2
IVD	NM_001354600.3		c.775-31T>C	intron	N/A	NP_001341529.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IVD	ENST00000487418.8	TSL:1 MANE Select	c.688-31T>C	intron	N/A	ENSP00000418397.3	A0A0A0MT83
IVD	ENST00000479013.7	TSL:1	c.598-31T>C	intron	N/A	ENSP00000417990.3	A0A0S2Z4K7
IVD	ENST00000868500.1		c.688-31T>C	intron	N/A	ENSP00000538559.1

Frequencies

GnomAD3 genomes

AF:

0.376

AC:

57097

AN:

151972

Hom.:

12099

Cov.:

show subpopulations

Gnomad AFR

AF:

0.205

Gnomad AMI

AF:

0.500

Gnomad AMR

AF:

0.458

Gnomad ASJ

AF:

0.427

Gnomad EAS

AF:

0.770

Gnomad SAS

AF:

0.625

Gnomad FIN

AF:

0.461

Gnomad MID

AF:

0.487

Gnomad NFE

AF:

0.395

Gnomad OTH

AF:

0.387

GnomAD2 exomes

AF:

0.467

AC:

117090

AN:

250492

AF XY:

0.474

show subpopulations

Gnomad AFR exome

AF:

0.203

Gnomad AMR exome

AF:

0.557

Gnomad ASJ exome

AF:

0.438

Gnomad EAS exome

AF:

0.776

Gnomad FIN exome

AF:

0.452

Gnomad NFE exome

AF:

0.394

Gnomad OTH exome

AF:

0.438

GnomAD4 exome

AF:

0.420

AC:

606054

AN:

1443176

Hom.:

134153

Cov.:

AF XY:

0.426

AC XY:

306508

AN XY:

719030

show subpopulations

African (AFR)

AF:

0.199

AC:

6567

AN:

33072

American (AMR)

AF:

0.546

AC:

24392

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.432

AC:

11251

AN:

26030

East Asian (EAS)

AF:

0.806

AC:

31926

AN:

39624

South Asian (SAS)

AF:

0.621

AC:

53403

AN:

85932

European-Finnish (FIN)

AF:

0.452

AC:

24096

AN:

53324

Middle Eastern (MID)

AF:

0.468

AC:

2654

AN:

5676

European-Non Finnish (NFE)

AF:

0.390

AC:

426768

AN:

1095124

Other (OTH)

AF:

0.418

AC:

24997

AN:

59758

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

17862

35723

53585

71446

89308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13474

26948

40422

53896

67370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.376

AC:

57128

AN:

152090

Hom.:

12105

Cov.:

AF XY:

0.386

AC XY:

28684

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.205

AC:

8497

AN:

41490

American (AMR)

AF:

0.459

AC:

7011

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.427

AC:

1482

AN:

3468

East Asian (EAS)

AF:

0.770

AC:

3987

AN:

5178

South Asian (SAS)

AF:

0.626

AC:

3020

AN:

4826

European-Finnish (FIN)

AF:

0.461

AC:

4873

AN:

10574

Middle Eastern (MID)

AF:

0.483

AC:

142

AN:

294

European-Non Finnish (NFE)

AF:

0.395

AC:

26844

AN:

67960

Other (OTH)

AF:

0.389

AC:

818

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1752

3504

5257

7009

8761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

568

1136

1704

2272

2840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.388

Hom.:

15678

Bravo

AF:

0.368

Asia WGS

AF:

0.602

AC:

2091

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Isovaleryl-CoA dehydrogenase deficiency (2)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

0.94

BranchPoint Hunter

4.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over