15-40407823-C-T

Variant names:

• chr15-40407823-C-T
• rs10518693
• NM_002225.5:c.234+98C>T

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.234+98C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 1,431,454 control chromosomes in the GnomAD database, including 132,847 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (12341 hom., cov: 31)
  • Exomes 𝑓: 0.42 (120506 hom.)
• Consequence: IVD NM_002225.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0380
• Publications: 40 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: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-40407823-C-T is Benign according to our data. Variant chr15-40407823-C-T is described in ClinVar as Benign. ClinVar VariationId is 1258387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IVD	NM_002225.5	c.234+98C>T		intron_variant	Intron 2 of 11	ENST00000487418.8	NP_002216.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IVD	ENST00000487418.8	c.234+98C>T		intron_variant	Intron 2 of 11	1	NM_002225.5	ENSP00000418397.3

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58120 AN: 151850 Hom.: 12334 Cov.: 31

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.769

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.390

GnomAD4 exome AF: 0.421 AC: 538606 AN: 1279484 Hom.: 120506 Cov.: 19 AF XY: 0.428 AC XY: 276342 AN XY: 645852

African (AFR) AF: 0.223 AC: 6648 AN: 29836

American (AMR) AF: 0.548 AC: 24307 AN: 44376

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 10757 AN: 24956

East Asian (EAS) AF: 0.806 AC: 31264 AN: 38770

South Asian (SAS) AF: 0.620 AC: 51123 AN: 82404

European-Finnish (FIN) AF: 0.452 AC: 24108 AN: 53312

Middle Eastern (MID) AF: 0.465 AC: 1983 AN: 4260

European-Non Finnish (NFE) AF: 0.386 AC: 365809 AN: 947394

Other (OTH) AF: 0.417 AC: 22607 AN: 54176

GnomAD4 genome AF: 0.383 AC: 58152 AN: 151970 Hom.: 12341 Cov.: 31 AF XY: 0.392 AC XY: 29108 AN XY: 74268

African (AFR) AF: 0.227 AC: 9403 AN: 41440

American (AMR) AF: 0.461 AC: 7042 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 1483 AN: 3468

East Asian (EAS) AF: 0.769 AC: 3971 AN: 5162

South Asian (SAS) AF: 0.623 AC: 3005 AN: 4820

European-Finnish (FIN) AF: 0.460 AC: 4851 AN: 10536

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.397 AC: 26972 AN: 67956

Other (OTH) AF: 0.393 AC: 828 AN: 2106

Alfa AF: 0.400 Hom.: 57744

Bravo AF: 0.376

Asia WGS AF: 0.602 AC: 2093 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.4
DANN	Benign	0.73
PhyloP100		0.038
PromoterAI		-0.030	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10518693; hg19: chr15-40700022;