dbSNP rs2289331: IVD:c.234+14T>C (chr15-40407739-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

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

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.60

Publications

18 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: 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

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

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.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.669

AC XY:

485153

AN XY:

725684

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

16718

33435

50153

66870

83588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18942

37884

56826

75768

94710

<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:

0.633

AC:

96287

AN:

152036

Hom.:

31248

Cov.:

AF XY:

0.644

AC XY:

47858

AN XY:

74348

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

1827

3654

5481

7308

9135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

794

1588

2382

3176

3970

<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:

0.641

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

View on ClinVar

Pathogenic

VUS

Benign

Condition

Isovaleryl-CoA dehydrogenase deficiency (5)

not specified (4)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.84

CADD

Benign

4.2

(source)

DANN

Benign

0.31

FATHMM_MKL

Benign

0.020

MetaRNN

Benign

0.0000011

PhyloP100

-1.6

Sift4G

Benign

0.21

GERP RS

-0.19

PromoterAI

0.052

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over