22-37735350-G-T

Position:

chr22-37735350-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

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U: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]

TRIOBP links:

Genome browser will be placed here

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, Uncertain_significance=1, Pathogenic=4, Likely_pathogenic=1}. 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/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3 linkuse as main transcript	c.5014G>T	p.Gly1672*	stop_gained	9/24	ENST00000644935.1	NP_001034230.1	Q9H2D6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TRIOBP	ENST00000644935.1 linkuse as main transcript	c.5014G>T	p.Gly1672*	stop_gained	9/24		NM_001039141.3	ENSP00000496394.1	Q9H2D6-1
TRIOBP	ENST00000344404.10 linkuse as main transcript	n.*4497G>T		non_coding_transcript_exon_variant	7/22	2		ENSP00000340312.6	H7BXW4
TRIOBP	ENST00000344404.10 linkuse as main transcript	n.*4497G>T		3_prime_UTR_variant	7/22	2		ENSP00000340312.6	H7BXW4

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152216

Hom.:

Cov.:

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.:

AF XY:

0.000463

AC XY:

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.:

Cov.:

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:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

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.:

Bravo

AF:

0.000317

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000477

AC:

ExAC

AF:

0.000498

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 09, 2022	PP1, PM2_supporting, PM3, PVS1 -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TRIOBP: PVS1, PM2 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal recessive nonsyndromic hearing loss 28

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 22, 2020

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

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 19, 2018

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

Uncertain significance, no assertion criteria provided

research

Center for Computational Biology & Bioinformatics, University of California, San Diego

Jun 03, 2024

- -

Hearing impairment

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PVS1_Strong, PM2_Supporting, BP4_Supporting, BP5_Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.069

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Uncertain

0.44

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.13

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over