12-108567650-G-C
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
Ensembl
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
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not provided Pathogenic:1
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. This variant is present in population databases (rs767000507, gnomAD 0.006%). 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. ClinVar contains an entry for this variant (Variation ID: 223141). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ISCU function (PMID: 18304497, 19846308, 30209894). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at