chr22-37710446-GTGCTGAGGTGCCCTAC-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001039141.3(TRIOBP):c.138_153del(p.Glu47ThrfsTer67) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000205 in 1,461,212 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
TRIOBP
NM_001039141.3 frameshift
NM_001039141.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.20
Genes affected
TRIOBP (HGNC:17009): (TRIO and F-actin binding protein) This gene encodes a protein with an N-terminal pleckstrin homology domain and a C-terminal coiled-coil region. The protein interacts with trio, which is involved with neural tissue development and controlling actin cytoskeleton organization, cell motility and cell growth. The protein also associates with F-actin and stabilizes F-actin structures. Mutations in this gene have been associated with a form of autosomal recessive nonsyndromic deafness. Multiple alternatively spliced transcript variants that would encode different isoforms have been found for this gene, however some transcripts may be subject to nonsense-mediated decay (NMD). [provided by RefSeq, Nov 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 22-37710446-GTGCTGAGGTGCCCTAC-G is Pathogenic according to our data. Variant chr22-37710446-GTGCTGAGGTGCCCTAC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3075891.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRIOBP | NM_001039141.3 | c.138_153del | p.Glu47ThrfsTer67 | frameshift_variant | 4/24 | ENST00000644935.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRIOBP | ENST00000644935.1 | c.138_153del | p.Glu47ThrfsTer67 | frameshift_variant | 4/24 | NM_001039141.3 | A2 | ||
TRIOBP | ENST00000492485.5 | n.274_289del | non_coding_transcript_exon_variant | 3/5 | 1 | ||||
TRIOBP | ENST00000344404.10 | c.138_153del | p.Glu47ThrfsTer39 | frameshift_variant, NMD_transcript_variant | 3/22 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
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GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248036Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134790
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461212Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 726952
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2022 | The p.Glu47ThrfsX67 variant in TRIOBP has not been reported in individuals with disease and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 47 and leads to a premature termination codon 67 amino acids downstream. Loss of function of the TRIOBP gene is an established disease mechanism in autosomal recessive hearing loss. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PM2_Supporting, PVS1. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at