rs766572502
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001352754.2(ARMC9):c.879G>A(p.Thr293=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,611,972 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 Likely pathogenic (★★).
Frequency
Consequence
NM_001352754.2 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARMC9 | NM_001352754.2 | c.879G>A | p.Thr293= | splice_region_variant, synonymous_variant | 9/25 | ENST00000611582.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARMC9 | ENST00000611582.5 | c.879G>A | p.Thr293= | splice_region_variant, synonymous_variant | 9/25 | 5 | NM_001352754.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000807 AC: 2AN: 247984Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133968
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1459750Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12AN XY: 726116
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74374
ClinVar
Submissions by phenotype
Joubert syndrome 30 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Mar 12, 2024 | The homozygous p.Thr293= variant in ARMC9 was identified by our study in two siblings with congenital fibrosis of the extraocular muscles, global developmental delay, situs inversus, and ciliary dyskinesia and in one unrelated individual with congenital fibrosis of the extraocular muscles and global developmental delay, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). The p.Thr293= variant in ARMC9 has been previously reported in two unrelated individuals with Joubert syndrome 30 (PMID: 29159890, PMID: 34716235) and segregated with disease in 3 affected relatives in one family (PMID: 29159890) but has been identified in 0.01% (1/10012) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs766572502). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. These affected individuals and the three affected individuals identified by our study were homozygotes, which increases the likelihood that the p.Thr293= variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 522606) and has been interpreted as pathogenic by Invitae and as likely pathogenic by Centre For DNA Fingerprinting and Diagnostics Diagnostics Division. In vitro assays provide some evidence that the p.Thr293= variant may slightly impact protein function (PMID: 29159890). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Joubert syndrome 30. ACMG/AMP Criteria applied: PS3_Supporting, PM2_Supporting, PM3, PP1, PP3 (Richards 2015). - |
Likely pathogenic, criteria provided, single submitter | research | Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS | Jan 01, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change affects codon 293 of the ARMC9 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ARMC9 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs766572502, gnomAD 0.01%). This variant has been observed in individual(s) with ARMC9-related conditions (PMID: 29159890). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 522606). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 9, but is expected to preserve the integrity of the reading-frame (PMID: 29159890). 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