rs1277466514

Positions:

chr22-37757794-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001039141.3(TRIOBP):c.5869C>T(p.Gln1957Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000194 in 1,547,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TRIOBP
NM_001039141.3 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:1

Conservation

PhyloP100: 2.53

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 10 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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TRIOBP	NM_001039141.3 linkuse as main transcript	c.5869C>T	p.Gln1957Ter	stop_gained	16/24	ENST00000644935.1	NP_001034230.1
TRIOBP	NM_007032.5 linkuse as main transcript	c.730C>T	p.Gln244Ter	stop_gained	6/14		NP_008963.3
TRIOBP	NM_138632.2 linkuse as main transcript	c.730C>T	p.Gln244Ter	stop_gained	6/8		NP_619538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1 linkuse as main transcript	c.5869C>T	p.Gln1957Ter	stop_gained	16/24		NM_001039141.3	ENSP00000496394	A2	Q9H2D6-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000134

AC:

AN:

149640

Hom.:

AF XY:

0.0000250

AC XY:

AN XY:

80106

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000810

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1395656

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

687964

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000560

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 08, 2016

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gln1957X variant in exon 16 of TRIOBP (NM_001039141.2) has not been previously reported i n individuals with hearing loss. Data from large population studies is insuffici ent to assess the frequency of this variant. This nonsense variant leads to a pr emature termination codon at position 1957 which is predicted to lead to a trunc ated or absent protein. However, several TRIOBP isoforms exist. In humans, a lon g isoform is reportedly expressed in the cochlea and a short isoform is ubiquito usly expressed (Kitajiri 2010). To date, all truncating or loss of function var iants in TRIOBP reported in individuals with hearing loss are located in exon 7 of the long isoform (NM_001039141.2), which does not overlap with exons in the s hort isoform. Furthermore, a mouse model showed that a homozygous deletion of th e exon 7 mouse homologue was profoundly deaf, but simultaneous knockout of both isoforms was embryonic lethal (Kitajiri 2010), suggesting that the long isoform is essential for hearing while the short isoform has an additional essential dev elopmental role in mice. However, biallelic truncating variants have not been re ported outside of exon 7 in patients with hearing loss, and biallelic truncating variants or loss of function variants that affect both isoforms have not been r eported in patients or individuals in control databases. In summary, while this variant is likely to result in a truncated or absent protein and may be disease causing, the clinical significance of this variant is uncertain due to limited d ata on truncating variants outside of exon 7 of the long isoform of the TRIOBP g ene. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.79

MutationTaster

Benign

1.0

A;A;A

Vest4

0.83

ClinPred

0.96

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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