dbSNP rs373594717: IVD:c.-9A>C (chr15-40405819-A-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002225.5(IVD):c.-9A>C 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 0.000000686 in 1,458,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IVD
NM_002225.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

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), Orphanet, Myriad Women’s Health, G2P, ClinGen

IVD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IVD	NM_002225.5 link	c.-9A>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 12	ENST00000487418.8	NP_002216.3	P26440A0A0A0MT83
IVD	NM_002225.5 link	c.-9A>C		5_prime_UTR_variant	Exon 1 of 12	ENST00000487418.8	NP_002216.3	P26440A0A0A0MT83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IVD	ENST00000487418.8 link	c.-9A>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 12	1	NM_002225.5	ENSP00000418397.3		A0A0A0MT83
IVD	ENST00000487418.8 link	c.-9A>C		5_prime_UTR_variant	Exon 1 of 12	1	NM_002225.5	ENSP00000418397.3		A0A0A0MT83

Frequencies

GnomAD3 genomes

Cov.:

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458580

Hom.:

Cov.:

AF XY:

0.00000138

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:

0.0000116

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:

0.00

AC:

AN:

1109706

Other (OTH)

AF:

0.00

AC:

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.018

BayesDel_noAF

Benign

-0.16

CADD

Benign

0.031

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.35

.;T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.060

LIST_S2

Uncertain

0.90

.;D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Uncertain

-0.19

PhyloP100

-3.5

PROVEAN

Benign

-0.060

.;N;N

REVEL

Benign

0.23

Sift

Pathogenic

0.0

.;D;D

Sift4G

Benign

0.25

T;T;T

Vest4

0.13, 0.16

MutPred

0.90

Gain of stability (P = 0.0076);Gain of stability (P = 0.0076);Gain of stability (P = 0.0076);

MVP

0.73

ClinPred

0.18

GERP RS

-8.8

PromoterAI

-0.12

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.71

Mutation Taster

=167/33

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over