2-231206294-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001352754.2(ARMC9):c.51+5G>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001352754.2 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARMC9 | NM_001352754.2 | c.51+5G>T | splice_donor_5th_base_variant, intron_variant | ENST00000611582.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARMC9 | ENST00000611582.5 | c.51+5G>T | splice_donor_5th_base_variant, intron_variant | 5 | NM_001352754.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1459940Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3AN XY: 726486
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74460
ClinVar
Submissions by phenotype
Joubert syndrome 30 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 04, 2022 | The heterozygous c.51+5G>T variant in ARMC9 was identified by our study in the compound heterozygous state, along with another variant of unknown significance, in 2 siblings with Joubert syndrome 30. The variant has also been reported in 1 Israeli individual with Joubert syndrome (PMID: 28625504), but was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 427931) as pathogenic by UW Hindbrain Malformation Research Program, University of Washington, and as likely pathogenic by University of Washington Center for Mendelian Genomics, University of Washington. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in 1 affected homozygote, and in 1 individual with Joubert syndrome 30 increases the likelihood that the c.51+5G>T variant is pathogenic (PMID: 28625504). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3_supporting (Richards 2015). - |
ARMC9-related Joubert syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | research | UW Hindbrain Malformation Research Program, University of Washington | May 01, 2017 | - - |
Familial aplasia of the vermis Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at