rs1555403942

Variant names:

• chr15-40410819-ACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGC-GTTG
• rs1555403942
• NM_002225.5:c.456+22_510delACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGCinsGTTG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_002225.5(IVD):​c.456+22_510delACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGCinsGTTG​(p.Leu153_Gly170del) variant causes a splice acceptor, conservative inframe deletion, splice region, synonymous, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L153L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IVD NM_002225.5 splice_acceptor, conservative_inframe_deletion, splice_region, synonymous, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.443
• 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: ClinGen, Orphanet, Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 15-40410819-ACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGC-GTTG is Pathogenic according to our data. Variant chr15-40410819-ACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGC-GTTG is described in ClinVar as Pathogenic. ClinVar VariationId is 459929.Status of the report is criteria_provided_single_submitter, 1 stars.

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.456+22_510delACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGCinsGTTG	p.Leu153_Gly170del	splice_acceptor conservative_inframe_deletion splice_region synonymous intron	Exon 5 of 12	NP_002216.3	A0A0A0MT83
	IVD	NM_001354601.3		c.456+22_510delACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGCinsGTTG	p.Leu153_Gly170del	splice_acceptor conservative_inframe_deletion splice_region synonymous intron	Exon 5 of 12	NP_001341530.2
	IVD	NM_001354600.3		c.543+22_597delACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGCinsGTTG	p.Leu182_Gly199del	splice_acceptor conservative_inframe_deletion splice_region synonymous intron	Exon 5 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.456+22_510delACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGCinsGTTG	p.Leu153_Gly170del	splice_acceptor conservative_inframe_deletion splice_region synonymous intron	Exon 5 of 12	ENSP00000418397.3	A0A0A0MT83
	IVD	ENST00000479013.7	TSL:1	c.366+22_420delACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGCinsGTTG	p.Leu123_Gly140del	splice_acceptor conservative_inframe_deletion splice_region synonymous intron	Exon 4 of 11	ENSP00000417990.3	A0A0S2Z4K7
	IVD	ENST00000868500.1		c.456+22_510delACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGCinsGTTG	p.Leu153_Gly170del	splice_acceptor conservative_inframe_deletion splice_region synonymous intron	Exon 5 of 13	ENSP00000538559.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Isovaleryl-CoA dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.44

Splicing

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

Other links and lift over

dbSNP: rs1555403942; hg19: chr15-40703018;