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

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00050 ( 1 hom. )

Consequence

TRIOBP
NM_001039141.3 stop_gained

Scores

1
3
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:2B:1

Conservation

PhyloP100: 0.891
Variant links:
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 11 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 22-37735350-G-T is Pathogenic according to our data. Variant chr22-37735350-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504691.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_benign=1, Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=4}. Variant chr22-37735350-G-T is described in Lovd as [Likely_pathogenic]. Variant chr22-37735350-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRIOBPNM_001039141.3 linkc.5014G>T p.Gly1672* stop_gained Exon 9 of 24 ENST00000644935.1 NP_001034230.1 Q9H2D6-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TRIOBPENST00000644935.1 linkc.5014G>T p.Gly1672* stop_gained Exon 9 of 24 NM_001039141.3 ENSP00000496394.1 Q9H2D6-1
TRIOBPENST00000344404.10 linkn.*4497G>T non_coding_transcript_exon_variant Exon 7 of 22 2 ENSP00000340312.6 H7BXW4
TRIOBPENST00000344404.10 linkn.*4497G>T 3_prime_UTR_variant Exon 7 of 22 2 ENSP00000340312.6 H7BXW4

Frequencies

GnomAD3 genomes
AF:
0.000388
AC:
59
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.000864
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000794
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000477
AC:
117
AN:
245176
Hom.:
0
AF XY:
0.000463
AC XY:
62
AN XY:
133858
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000146
Gnomad ASJ exome
AF:
0.00171
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.000428
Gnomad NFE exome
AF:
0.000761
Gnomad OTH exome
AF:
0.000168
GnomAD4 exome
AF:
0.000499
AC:
729
AN:
1460830
Hom.:
1
Cov.:
35
AF XY:
0.000473
AC XY:
344
AN XY:
726692
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00180
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.000303
Gnomad4 NFE exome
AF:
0.000570
Gnomad4 OTH exome
AF:
0.000431
GnomAD4 genome
AF:
0.000387
AC:
59
AN:
152334
Hom.:
0
Cov.:
33
AF XY:
0.000336
AC XY:
25
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.000864
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000794
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000802
Hom.:
0
Bravo
AF:
0.000317
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000477
AC:
4
ExAC
AF:
0.000498
AC:
60
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000382
EpiControl
AF:
0.000594

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:8Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:6
Mar 09, 2022
Mayo Clinic Laboratories, Mayo Clinic
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP1, PM2_supporting, PM3, PVS1 -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jan 26, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

TRIOBP: PVS1, PM2 -

Autosomal recessive nonsyndromic hearing loss 28 Pathogenic:2
Sep 22, 2020
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jan 31, 2023
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

not specified Uncertain:1
Dec 19, 2018
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jun 03, 2024
Center for Computational Biology & Bioinformatics, University of California, San Diego
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Hearing impairment Benign:1
Apr 12, 2021
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center
Significance: Likely benign
Review Status: flagged submission
Collection Method: clinical testing

PVS1_Strong, PM2_Supporting, BP4_Supporting, BP5_Supporting -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.069
T
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
36
DANN
Uncertain
0.98
Eigen
Uncertain
0.44
Eigen_PC
Benign
0.13
FATHMM_MKL
Benign
0.13
N
Vest4
0.69
GERP RS
1.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200045032; hg19: chr22-38131357; API