NM_002225.5:c.688-31T>C

Variant names:

• chr15-40412960-T-C
• rs2289329
• NM_002225.5:c.688-31T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.944
• Publications: 22 publications found

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

ACMG classification

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 CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id is 258591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40412960-T-C is described in CliVar as Benign. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IVD	NM_002225.5	c.688-31T>C		intron_variant	Intron 6 of 11	ENST00000487418.8	NP_002216.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IVD	ENST00000487418.8	c.688-31T>C		intron_variant	Intron 6 of 11	1	NM_002225.5	ENSP00000418397.3

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57097 AN: 151972 Hom.: 12099 Cov.: 33

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

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.: 27 AF XY: 0.426 AC XY: 306508 AN XY: 719030

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

GnomAD4 genome AF: 0.376 AC: 57128 AN: 152090 Hom.: 12105 Cov.: 33 AF XY: 0.386 AC XY: 28684 AN XY: 74352

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

Alfa AF: 0.388 Hom.: 15678

Bravo AF: 0.368

Asia WGS AF: 0.602 AC: 2091 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

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	-0.84
CADD	Benign	15
DANN	Benign	0.76
PhyloP100		0.94
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2289329; hg19: chr15-40705159; COSMIC: COSV107220736; COSMIC: COSV107220736;