NM_002225.5:c.1065+41A>G

Variant names:

• chr15-40416223-A-G
• rs11070270
• NM_002225.5:c.1065+41A>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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.489
• Publications: 14 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=-0.86).
• BP6: Variant 15-40416223-A-G is Benign according to our data. Variant chr15-40416223-A-G is described in ClinVar as Benign. ClinVar VariationId 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.

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.1065+41A>G		intron	N/A	NP_002216.3	A0A0A0MT83
	IVD	NM_001354601.3		c.1065+41A>G		intron	N/A	NP_001341530.2
	IVD	NM_001354600.3		c.1152+41A>G		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.1065+41A>G		intron	N/A	ENSP00000418397.3	A0A0A0MT83
	IVD	ENST00000479013.7	TSL:1	c.975+41A>G		intron	N/A	ENSP00000417990.3	A0A0S2Z4K7
	IVD	ENST00000497816.1	TSL:1	n.442+41A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.618 AC: 93920 AN: 152088 Hom.: 30130 Cov.: 34

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

GnomAD2 exomes AF: 0.683 AC: 170313 AN: 249326 AF XY: 0.689

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 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.: 34 AF XY: 0.667 AC XY: 484529 AN XY: 726090

African (AFR) AF: 0.431 AC: 14411 AN: 33438

American (AMR) AF: 0.689 AC: 30745 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 17495 AN: 26122

East Asian (EAS) AF: 0.835 AC: 33116 AN: 39658

South Asian (SAS) AF: 0.750 AC: 64685 AN: 86212

European-Finnish (FIN) AF: 0.807 AC: 42890 AN: 53154

Middle Eastern (MID) AF: 0.632 AC: 3640 AN: 5758

European-Non Finnish (NFE) AF: 0.651 AC: 722197 AN: 1110072

Other (OTH) AF: 0.657 AC: 39603 AN: 60314

GnomAD4 genome AF: 0.618 AC: 93990 AN: 152206 Hom.: 30154 Cov.: 34 AF XY: 0.629 AC XY: 46829 AN XY: 74428

African (AFR) AF: 0.440 AC: 18272 AN: 41522

American (AMR) AF: 0.667 AC: 10205 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 2324 AN: 3470

East Asian (EAS) AF: 0.806 AC: 4166 AN: 5170

South Asian (SAS) AF: 0.751 AC: 3619 AN: 4822

European-Finnish (FIN) AF: 0.825 AC: 8764 AN: 10618

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.655 AC: 44542 AN: 67996

Other (OTH) AF: 0.612 AC: 1294 AN: 2114

Alfa AF: 0.640 Hom.: 14910

Bravo AF: 0.597

Asia WGS AF: 0.719 AC: 2501 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Isovaleryl-CoA dehydrogenase deficiency (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.7
DANN	Benign	0.44
PhyloP100		0.49
PromoterAI		0.022	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11070270; hg19: chr15-40708422; COSMIC: COSV51101873; COSMIC: COSV51101873;