rs118204027

Positions:

• chr22-37724297-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001039141.3(TRIOBP):​c.1741C>T​(p.Gln581Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 15)
• Consequence: TRIOBP NM_001039141.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.99

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 12 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 22-37724297-C-T is Pathogenic according to our data. Variant chr22-37724297-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1491.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-37724297-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.1741C>T	p.Gln581Ter	stop_gained	7/24	ENST00000644935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.1741C>T	p.Gln581Ter	stop_gained	7/24		NM_001039141.3	A2
TRIOBP	ENST00000492485.5	n.1675C>T		non_coding_transcript_exon_variant	5/5	1
TRIOBP	ENST00000344404.10	c.*1224C>T		3_prime_UTR_variant, NMD_transcript_variant	5/22	2

Frequencies

GnomAD3 genomes Cov.: 15

GnomAD4 exome Cov.: 143

GnomAD4 genome Cov.: 15

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 28 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2006

- -

Nonsyndromic genetic hearing loss Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 02, 2023

The p.Gln581X variant in TRIOBP has been reported in >10 Palestinian individuals with nonsyndromic hearing loss as either homozygous or compound heterozygous with a second pathogenic variant, and segregated with hearing loss in several family members (Shahin 2006 PMID 16385458, Abu Rayyan 2020 PMID 32747562). The variant is absent in large population databases. This nonsense variant leads to a premature termination codon at position 581, which is predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss. PVS1, PM3_Strong, PP1_Strong. (This variant did not meet the variant calling quality criteria, and was included because it has been previously reported as a clinically significant variant.) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Uncertain	0.23
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.034	N
MutationTaster	Benign	1.0	A
Vest4		0.43
GERP RS		3.5

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

Other links and lift over

dbSNP: rs118204027; hg19: chr22-38120304;