chr15-40407639-C-A

Variant names:

• chr15-40407639-C-A
• rs34695403
• NM_002225.5:c.148C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_002225.5(IVD):​c.148C>A​(p.Arg50Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R50G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IVD NM_002225.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.65
• 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), Orphanet, Myriad Women’s Health, G2P, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_002225.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-40407639-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 648047.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IVD	NM_002225.5	MANE Select	c.148C>A	p.Arg50Ser	missense	Exon 2 of 12	NP_002216.3
	IVD	NM_001354601.3		c.148C>A	p.Arg50Ser	missense	Exon 2 of 12	NP_001341530.2
	IVD	NM_001354600.3		c.148C>A	p.Arg50Ser	missense	Exon 2 of 13	NP_001341529.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IVD	ENST00000487418.8	TSL:1 MANE Select	c.148C>A	p.Arg50Ser	missense	Exon 2 of 12	ENSP00000418397.3
	IVD	ENST00000479013.7	TSL:1	c.145-300C>A		intron	N/A	ENSP00000417990.3
	IVD	ENST00000651168.1		c.157C>A	p.Arg53Ser	missense	Exon 2 of 12	ENSP00000499074.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461374 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727042

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111552

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.97	D
PhyloP100		3.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.91
MVP		0.96
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		-0.0032	Neutral
Varity_R		0.98
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34695403; hg19: chr15-40699840;