22-37723595-C-T

Position:

chr22-37723595-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001039141.3(TRIOBP):c.1039C>T(p.Arg347*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

TRIOBP
NM_001039141.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.202

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:

ENSG00000100101 (HGNC:):

ENSG00000100101 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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 22-37723595-C-T is Pathogenic according to our data. Variant chr22-37723595-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37723595-C-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.1039C>T	p.Arg347*	stop_gained	7/24	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.1039C>T	p.Arg347*	stop_gained	7/24		NM_001039141.3	ENSP00000496394.1	Q9H2D6-1
ENSG00000100101	ENST00000455236.4 linkuse as main transcript	n.*1375C>T		non_coding_transcript_exon_variant	13/13	5		ENSP00000477208.1	V9GYY5
ENSG00000100101	ENST00000455236.4 linkuse as main transcript	n.*1375C>T		3_prime_UTR_variant	13/13	5		ENSP00000477208.1	V9GYY5

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000281

AC:

AN:

249550

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135388

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461886

Hom.:

Cov.:

102

AF XY:

0.0000413

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000441

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000569

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000414

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 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: 25525159, 30833958, 32747562, 33121024, 16385458, 32279305) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2023	This sequence change creates a premature translational stop signal (p.Arg347*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1490). This premature translational stop signal has been observed in individual(s) with nonsyndromic deafness (PMID: 16385458). This variant is present in population databases (rs118204026, gnomAD 0.01%). -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jan 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2017	- -

Autosomal recessive nonsyndromic hearing loss 28

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. This variant has been reported as pathogenic (ClinVar ID: VCV000001490, PMID:16385458). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000399). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2006	- -
Pathogenic, no assertion criteria provided	research	Hereditary Research Laboratory, Bethlehem University	Jun 04, 2016	Severe to Profound -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Benign

0.91

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.024

Vest4

0.55

GERP RS

-0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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