15-40407720-C-T

Variant names:

• chr15-40407720-C-T
• rs143807229
• NM_002225.5:c.229C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_002225.5(IVD):​c.229C>T​(p.Leu77Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.000606 in 1,614,030 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (9 hom.)
• Consequence: IVD NM_002225.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.03
• Publications: 0 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 15-40407720-C-T is Benign according to our data. Variant chr15-40407720-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 382411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000453 (69/152328) while in subpopulation SAS AF = 0.00539 (26/4822). AF 95% confidence interval is 0.00378. There are 0 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

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.229C>T	p.Leu77Leu	synonymous	Exon 2 of 12	NP_002216.3	A0A0A0MT83
	IVD	NM_001354601.3		c.229C>T	p.Leu77Leu	synonymous	Exon 2 of 12	NP_001341530.2
	IVD	NM_001354600.3		c.229C>T	p.Leu77Leu	synonymous	Exon 2 of 13	NP_001341529.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IVD	ENST00000487418.8	TSL:1 MANE Select	c.229C>T	p.Leu77Leu	synonymous	Exon 2 of 12	ENSP00000418397.3	A0A0A0MT83
	IVD	ENST00000479013.7	TSL:1	c.145-219C>T		intron	N/A	ENSP00000417990.3	A0A0S2Z4K7
	IVD	ENST00000868500.1		c.229C>T	p.Leu77Leu	synonymous	Exon 2 of 13	ENSP00000538559.1

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000927 AC: 233 AN: 251468 AF XY: 0.00119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000642

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000622 AC: 909 AN: 1461702 Hom.: 9 Cov.: 31 AF XY: 0.000784 AC XY: 570 AN XY: 727170

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00422 AC: 364 AN: 86232

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53414

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5750

European-Non Finnish (NFE) AF: 0.000365 AC: 406 AN: 1111882

Other (OTH) AF: 0.00109 AC: 66 AN: 60384

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000564 AC XY: 42 AN XY: 74490

African (AFR) AF: 0.0000481 AC: 2 AN: 41580

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000514 AC: 35 AN: 68028

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000320 Hom.: 0

Bravo AF: 0.000306

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	-0.38
CADD	Benign	8.4
DANN	Benign	0.82
PhyloP100		4.0
PromoterAI		0.0091	Neutral
Mutation Taster		=99/1	polymorphism

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: rs143807229; hg19: chr15-40699921;