22-37735350-G-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_001039141.3(TRIOBP):c.5014G>T(p.Gly1672*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000488 in 1,613,164 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001039141.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TRIOBP | ENST00000644935.1 | c.5014G>T | p.Gly1672* | stop_gained | Exon 9 of 24 | NM_001039141.3 | ENSP00000496394.1 | |||
TRIOBP | ENST00000344404.10 | n.*4497G>T | non_coding_transcript_exon_variant | Exon 7 of 22 | 2 | ENSP00000340312.6 | ||||
TRIOBP | ENST00000344404.10 | n.*4497G>T | 3_prime_UTR_variant | Exon 7 of 22 | 2 | ENSP00000340312.6 |
Frequencies
GnomAD3 genomes AF: 0.000388 AC: 59AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000477 AC: 117AN: 245176Hom.: 0 AF XY: 0.000463 AC XY: 62AN XY: 133858
GnomAD4 exome AF: 0.000499 AC: 729AN: 1460830Hom.: 1 Cov.: 35 AF XY: 0.000473 AC XY: 344AN XY: 726692
GnomAD4 genome AF: 0.000387 AC: 59AN: 152334Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25AN XY: 74488
ClinVar
Submissions by phenotype
not provided Pathogenic:6
PP1, PM2_supporting, PM3, PVS1 -
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This sequence change creates a premature translational stop signal (p.Gly1672*) in the TRIOBP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TRIOBP are known to be pathogenic (PMID: 16385457, 16385458, 20510926). This variant is present in population databases (rs200045032, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with deafness (PMID: 28000701, 28089734, 29197352). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 504691). For these reasons, this variant has been classified as Pathogenic. -
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29197352, 28089734, 34426522, 28000701) -
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TRIOBP: PVS1, PM2 -
Autosomal recessive nonsyndromic hearing loss 28 Pathogenic:2
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
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not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly1672X variant in exon 9 of TRIOBP has been reported in compound heterozygous state wit h frameshift variants in exon 7 (NM_001039141.2) in 2 individuals hearing loss ( Pollack 2017, Wesdorp 2017, Zazo-Seco 2017). This variant has also been identifi ed in 0.17% (17/10060) of Ashkenazi Jewish chromosomes and 0.08% (98/124714) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1672 which is predic ted to lead to a truncated or absent protein; however, there are several alterna tely spliced TRIOBP isoforms in humans. All pathogenic truncating variants in T RIOBP reported to date have been identified in exon 7, which is common in both t he TRIOBP-5 and TRIOBP-4 transcripts. The p.Gly1672X variant occurs in exon 9 of the TRIOBP-5 transcript. It is unknown at this time if truncating variants imp acting only the TRIOBP-5 transcript are causative for hearing loss. In summary, while there is some suspicion for a pathogenic role, the clinical significance o f the p.Gly1672X variant is uncertain. ACMG/AMP Criteria applied: PM3, BS1_Suppo rting. -
Meniere disease Uncertain:1
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Hearing impairment Benign:1
PVS1_Strong, PM2_Supporting, BP4_Supporting, BP5_Supporting -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at