15-40405819-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_002225.5(IVD):c.-9A>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 0.00000435 in 1,610,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

IVD
NM_002225.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: -3.48

Publications

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

IVD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.847

PP5

Variant 15-40405819-A-T is Pathogenic according to our data. Variant chr15-40405819-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 552811.

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.-9A>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_002216.3	A0A0A0MT83
IVD	NM_002225.5	MANE Select	c.-9A>T	5_prime_UTR	Exon 1 of 12	NP_002216.3	A0A0A0MT83
IVD	NM_001354601.3		c.-9A>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_001341530.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IVD	ENST00000487418.8	TSL:1 MANE Select	c.-9A>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000418397.3	A0A0A0MT83
IVD	ENST00000479013.7	TSL:1	c.-9A>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000417990.3	A0A0S2Z4K7
IVD	ENST00000487418.8	TSL:1 MANE Select	c.-9A>T	5_prime_UTR	Exon 1 of 12	ENSP00000418397.3	A0A0A0MT83

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249662

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1458580

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724960

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33388

American (AMR)

AF:

0.00

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.00

AC:

AN:

86124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5560

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1109706

Other (OTH)

AF:

0.0000166

AC:

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41478

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Isovaleryl-CoA dehydrogenase deficiency (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.052

BayesDel_noAF

Benign

-0.16

CADD

Benign

0.024

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.35

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.10

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

-0.19

PhyloP100

-3.5

PROVEAN

Benign

-0.060

REVEL

Benign

0.23

Sift

Pathogenic

0.0

Sift4G

Benign

0.25

Vest4

0.13

MutPred

0.90

Gain of stability (P = 0.0076)

MVP

0.73

ClinPred

0.20

GERP RS

-8.8

PromoterAI

-0.21

Neutral

(source)

Varity_R

0.71

Mutation Taster

=167/33

disease causing (ClinVar)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over