Genetic Variant IVD:c.1065+41A>G (chr15-40416223-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002225.5(IVD):c.1065+41A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.659 in 1,611,534 control chromosomes in the GnomAD database, including 354,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 30154 hom., cov: 34)

Exomes 𝑓: 0.66 ( 324255 hom. )

Consequence

IVD
NM_002225.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.489

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 15-40416223-A-G is Benign according to our data. Variant chr15-40416223-A-G is described in ClinVar as [Benign]. Clinvar id is 258590.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IVD	NM_002225.5 link	c.1065+41A>G		intron_variant	Intron 10 of 11	ENST00000487418.8	NP_002216.3	P26440A0A0A0MT83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IVD	ENST00000487418.8 link	c.1065+41A>G		intron_variant	Intron 10 of 11	1	NM_002225.5	ENSP00000418397.3		A0A0A0MT83

Frequencies

GnomAD3 genomes

AF:

0.618

AC:

93920

AN:

152088

Hom.:

30130

Cov.:

show subpopulations

Gnomad AFR

AF:

0.440

Gnomad AMI

AF:

0.681

Gnomad AMR

AF:

0.667

Gnomad ASJ

AF:

0.670

Gnomad EAS

AF:

0.805

Gnomad SAS

AF:

0.750

Gnomad FIN

AF:

0.825

Gnomad MID

AF:

0.633

Gnomad NFE

AF:

0.655

Gnomad OTH

AF:

0.612

GnomAD3 exomes

AF:

0.683

AC:

170313

AN:

249326

Hom.:

59096

AF XY:

0.689

AC XY:

92863

AN XY:

134800

show subpopulations

Gnomad AFR exome

AF:

0.441

Gnomad AMR exome

AF:

0.694

Gnomad ASJ exome

AF:

0.677

Gnomad EAS exome

AF:

0.813

Gnomad SAS exome

AF:

0.749

Gnomad FIN exome

AF:

0.807

Gnomad NFE exome

AF:

0.654

Gnomad OTH exome

AF:

0.667

GnomAD4 exome

AF:

0.664

AC:

968782

AN:

1459328

Hom.:

324255

Cov.:

AF XY:

0.667

AC XY:

484529

AN XY:

726090

show subpopulations

Gnomad4 AFR exome

AF:

0.431

Gnomad4 AMR exome

AF:

0.689

Gnomad4 ASJ exome

AF:

0.670

Gnomad4 EAS exome

AF:

0.835

Gnomad4 SAS exome

AF:

0.750

Gnomad4 FIN exome

AF:

0.807

Gnomad4 NFE exome

AF:

0.651

Gnomad4 OTH exome

AF:

0.657

GnomAD4 genome

AF:

0.618

AC:

93990

AN:

152206

Hom.:

30154

Cov.:

AF XY:

0.629

AC XY:

46829

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.440

Gnomad4 AMR

AF:

0.667

Gnomad4 ASJ

AF:

0.670

Gnomad4 EAS

AF:

0.806

Gnomad4 SAS

AF:

0.751

Gnomad4 FIN

AF:

0.825

Gnomad4 NFE

AF:

0.655

Gnomad4 OTH

AF:

0.612

Alfa

AF:

0.642

Hom.:

12648

Bravo

AF:

0.597

Asia WGS

AF:

0.719

AC:

2501

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Isovaleryl-CoA dehydrogenase deficiency

Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 12, 2018

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

5.7

DANN

Benign

0.44

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over