22-37701476-C-G

Position:

• chr22-37701476-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001039141.3(TRIOBP):​c.111C>G​(p.Tyr37Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,784 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: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TRIOBP NM_001039141.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0880

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]

ACMG classification

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	UniProt
TRIOBP	NM_001039141.3	c.111C>G	p.Tyr37Ter	stop_gained	3/24	ENST00000644935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.111C>G	p.Tyr37Ter	stop_gained	3/24		NM_001039141.3	A2
TRIOBP	ENST00000492485.5	n.247C>G		non_coding_transcript_exon_variant	2/5	1
TRIOBP	ENST00000344404.10	c.111C>G	p.Tyr37Ter	stop_gained, NMD_transcript_variant	2/22	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455784 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723754

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

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 Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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 11, 2015

The p.Tyr37X variant in TRIOBP (exon 3 in NM_001039141.2) has not been previousl y reported in individuals with hearing loss and was absent from large population studies. This nonsense variant leads to a premature termination codon at positi on 37, which is predicted to lead to a truncated or absent protein. However, the variant affects the coding region of only one transcript isoform of the TRIOBP gene, and lies in the non-coding region of another transcript isoform and in the intragenic region of two isoforms (Riazuddin 2006). Pathogenic variants in exon 3 of this isoform have not been reported in affected individuals, and the major ity of reported pathogenic variants occur in exon 7 of this isoform, which also impact a coding exon of an alternate isoform. Therefore, it is not clear whether loss of function variants that impact this isoform only are causative for heari ng loss, or if both of these isoforms must be affected to cause hearing loss. In summary, the clinical significance of the p.Tyr37X variant in the NM_001039141. 2 transcript isoform of TRIOBP is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.069
FATHMM_MKL	Benign	0.16	N
MutationTaster	Benign	1.0	A
Vest4		0.33
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs876658035; hg19: chr22-38097483; COSMIC: COSV60381569;