rs118204029

chr22-37724918-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001039141.3(TRIOBP):c.2362C>T(p.Arg788Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: TRIOBP NM_001039141.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0130

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 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 22-37724918-C-T is Pathogenic according to our data. Variant chr22-37724918-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1493.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-37724918-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.2362C>T	p.Arg788Ter	stop_gained	7/24	ENST00000644935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.2362C>T	p.Arg788Ter	stop_gained	7/24		NM_001039141.3	A2
TRIOBP	ENST00000492485.5	n.2296C>T		non_coding_transcript_exon_variant	5/5	1
TRIOBP	ENST00000344404.10	c.*1845C>T		3_prime_UTR_variant, NMD_transcript_variant	5/22	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 249572 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135406

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: 0.0000928

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461780 Hom.: 0 Cov.: 147 AF XY: 0.00000413 AC XY: 3 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000331 AC: 4

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 28 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	28
Dann	Uncertain	0.98
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.013	N
MutationTaster	Benign	1.0	A
Vest4		0.40
GERP RS		-2.6

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: rs118204029; hg19: chr22-38120925;