rs767000507
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_213595.4(ISCU):c.418+382G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000606 in 1,535,182 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000067 ( 1 hom. )
Consequence
ISCU
NM_213595.4 intron
NM_213595.4 intron
Scores
2
Splicing: ADA: 0.00009216
2
Clinical Significance
Conservation
PhyloP100: 1.22
Genes affected
ISCU (HGNC:29882): (iron-sulfur cluster assembly enzyme) This gene encodes a component of the iron-sulfur (Fe-S) cluster scaffold. Fe-S clusters are cofactors that play a role in the function of a diverse set of enzymes, including those that regulate metabolism, iron homeostasis, and oxidative stress response. Alternative splicing results in transcript variants encoding different protein isoforms that localize either to the cytosol or to the mitochondrion. Mutations in this gene have been found in patients with hereditary myopathy with lactic acidosis. A disease-associated mutation in an intron may activate a cryptic splice site, resulting in the production of a splice variant encoding a putatively non-functional protein. A pseudogene of this gene is present on chromosome 1. [provided by RefSeq, Feb 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-108567650-G-C is Pathogenic according to our data. Variant chr12-108567650-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 223141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-108567650-G-C is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.83). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ISCU | NM_213595.4 | c.418+382G>C | intron_variant | ENST00000311893.14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ISCU | ENST00000311893.14 | c.418+382G>C | intron_variant | 1 | NM_213595.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000224 AC: 3AN: 134050Hom.: 0 AF XY: 0.0000137 AC XY: 1AN XY: 73118
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GnomAD4 exome AF: 0.0000665 AC: 92AN: 1382960Hom.: 1 Cov.: 30 AF XY: 0.0000557 AC XY: 38AN XY: 682526
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74368
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary myopathy with lactic acidosis due to ISCU deficiency Pathogenic:2Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Apr 07, 2021 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 08, 2021 | This variant has been observed in individuals with hereditary myopathy with lactic acidosis (PMID: 18296749, 18304497, 20206689). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs767000507, gnomAD 0.006%). This sequence change falls in intron 4 of the ISCU gene. It does not directly change the encoded amino acid sequence of the ISCU protein. ClinVar contains an entry for this variant (Variation ID: 223141). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects ISCU function (PMID: 18304497, 19846308, 30209894). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at