rs115077254

Variant names:

• chr15-40416285-C-T
• rs115077254
• NM_002225.5:c.1066-5C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-40416285-C-T
• chr15-40416285-C-G

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.1066-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,614,200 control chromosomes in the GnomAD database, including 238 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (99 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (139 hom.)
• Consequence: IVD NM_002225.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003376
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.759
• Publications: 1 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), Myriad Women’s Health, ClinGen, G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 15-40416285-C-T is Benign according to our data. Variant chr15-40416285-C-T is described in ClinVar as Benign. ClinVar VariationId is 315803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0646 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002225.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IVD	NM_002225.5	MANE Select	c.1066-5C>T		splice_region intron	N/A	NP_002216.3	A0A0A0MT83
	IVD	NM_001354601.3		c.1066-5C>T		splice_region intron	N/A	NP_001341530.2
	IVD	NM_001354600.3		c.1153-5C>T		splice_region intron	N/A	NP_001341529.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IVD	ENST00000487418.8	TSL:1 MANE Select	c.1066-5C>T		splice_region intron	N/A	ENSP00000418397.3	A0A0A0MT83
	IVD	ENST00000479013.7	TSL:1	c.976-5C>T		splice_region intron	N/A	ENSP00000417990.3	A0A0S2Z4K7
	IVD	ENST00000497816.1	TSL:1	n.443-5C>T		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3122 AN: 152246 Hom.: 99 Cov.: 32

Gnomad AFR AF: 0.0669

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0401

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00763 AC: 1918 AN: 251456 AF XY: 0.00605

Gnomad AFR exome AF: 0.0667

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0390

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00295 AC: 4315 AN: 1461838 Hom.: 139 Cov.: 33 AF XY: 0.00269 AC XY: 1957 AN XY: 727222

African (AFR) AF: 0.0706 AC: 2365 AN: 33476

American (AMR) AF: 0.00255 AC: 114 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0362 AC: 1438 AN: 39698

South Asian (SAS) AF: 0.000603 AC: 52 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5764

European-Non Finnish (NFE) AF: 0.0000639 AC: 71 AN: 1111980

Other (OTH) AF: 0.00439 AC: 265 AN: 60392

GnomAD4 genome AF: 0.0205 AC: 3120 AN: 152362 Hom.: 99 Cov.: 32 AF XY: 0.0198 AC XY: 1476 AN XY: 74508

African (AFR) AF: 0.0667 AC: 2772 AN: 41584

American (AMR) AF: 0.00594 AC: 91 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0400 AC: 207 AN: 5180

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68044

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.00869 Hom.: 34

Bravo AF: 0.0233

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Isovaleryl-CoA dehydrogenase deficiency (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.5
DANN	Benign	0.70
PhyloP100		-0.76
PromoterAI		-0.0064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.010		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: rs115077254; hg19: chr15-40708484;