rs754639936
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_001195518.2(MICU1):c.1072-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,607,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001195518.2 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MICU1 | NM_001195518.2 | c.1072-1G>C | splice_acceptor_variant | ENST00000361114.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MICU1 | ENST00000361114.10 | c.1072-1G>C | splice_acceptor_variant | 1 | NM_001195518.2 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000525 AC: 13AN: 247640Hom.: 0 AF XY: 0.0000744 AC XY: 10AN XY: 134390
GnomAD4 exome AF: 0.0000240 AC: 35AN: 1455458Hom.: 0 Cov.: 27 AF XY: 0.0000331 AC XY: 24AN XY: 724412
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Proximal myopathy with extrapyramidal signs Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | A Heterozygous Intron, Splice site acceptor variant c.1078-1G>C in Exon 10 of the MICU1 gene that results in the amino acid substitution was identified. The observed variant has a minor allele frequency of 0.00005% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (variant id: 101045). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The splice site variant c.1072-1G>C has been reported previously in affected individuals (Logan CV et.al.,2014). This variant has been reported to the ClinVar database as Pathogenic. The c.1072-1G>C variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.005250% is reported in gnomAD. The variant affects an invariant splice nucleotide and is expected to cause loss of function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 20, 2022 | Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24336167, 28132899) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at