rs767000507
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_001301140.1(ISCU):c.419-8G>C variant causes a splice region, 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001301140.1 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ISCU | NM_213595.4 | c.418+382G>C | intron_variant | ENST00000311893.14 | NP_998760.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ISCU | ENST00000311893.14 | c.418+382G>C | intron_variant | 1 | NM_213595.4 | ENSP00000310623.9 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000224 AC: 3AN: 134050Hom.: 0 AF XY: 0.0000137 AC XY: 1AN XY: 73118
GnomAD4 exome AF: 0.0000665 AC: 92AN: 1382960Hom.: 1 Cov.: 30 AF XY: 0.0000557 AC XY: 38AN XY: 682526
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74368
ClinVar
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 | Labcorp Genetics (formerly Invitae), Labcorp | 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at