rs121434447
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_012210.4(TRIM32):c.1181G>A(p.Arg394His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R394C) has been classified as Uncertain significance.
Frequency
Consequence
NM_012210.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRIM32 | NM_012210.4 | c.1181G>A | p.Arg394His | missense_variant | 2/2 | ENST00000450136.2 | |
ASTN2 | NM_001365068.1 | c.2806+26848C>T | intron_variant | ENST00000313400.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRIM32 | ENST00000450136.2 | c.1181G>A | p.Arg394His | missense_variant | 2/2 | 1 | NM_012210.4 | P1 | |
ASTN2 | ENST00000313400.9 | c.2806+26848C>T | intron_variant | 5 | NM_001365068.1 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251274Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135848
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461888Hom.: 0 Cov.: 30 AF XY: 0.0000289 AC XY: 21AN XY: 727244
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74350
ClinVar
Submissions by phenotype
Sarcotubular myopathy Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The heterozygous p.Arg394His variant in TRIM32 was identified by our study in the compound heterozygous state, with a VUS, in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.003658% (9/246046) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121434447). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. 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 vitro functional studies provide some evidence that the p.Arg394His variant may impact protein function by affecting its localization, homodimerization, and ubiquitin ligase activity (PMID: 19349376, 17994549). However, these types of assays may not accurately represent biological function. The p.Arg394His variant in TRIM32 has been reported in 2 individuals with LGMD in the literature (PMID: 17994549). This variant has also been reported in ClinVar (Variation ID: 7353). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS3_Moderate (Richards 2015). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2009 | - - |
Bardet-Biedl syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 394 of the TRIM32 protein (p.Arg394His). This variant is present in population databases (rs121434447, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of limb-girdle muscular dystrophy (PMID: 17994549; Invitae). ClinVar contains an entry for this variant (Variation ID: 7353). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TRIM32 function (PMID: 17994549, 19349376, 33296226). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Bardet-Biedl syndrome 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 13, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 03, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at