NM_001039141.3:c.115-35C>T

Variant names:

• chr22-37710392-C-T
• rs145499943
• NM_001039141.3:c.115-35C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001039141.3(TRIOBP):​c.115-35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,611,398 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (18 hom.)
• Consequence: TRIOBP NM_001039141.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.755
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 28

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ENSG00000100101 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 22-37710392-C-T is Benign according to our data. Variant chr22-37710392-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1215413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00378 (576/152344) while in subpopulation NFE AF = 0.00398 (271/68012). AF 95% confidence interval is 0.00359. There are 5 homozygotes in GnomAd4. There are 327 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.115-35C>T		intron_variant	Intron 3 of 23	ENST00000644935.1	NP_001034230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.115-35C>T		intron_variant	Intron 3 of 23		NM_001039141.3	ENSP00000496394.1
ENSG00000100101	ENST00000455236.4	n.*451-35C>T		intron_variant	Intron 9 of 12	5		ENSP00000477208.1
TRIOBP	ENST00000492485.5	n.251-35C>T		intron_variant	Intron 2 of 4	1
TRIOBP	ENST00000344404.10	n.115-35C>T		intron_variant	Intron 2 of 21	2		ENSP00000340312.6

Frequencies

GnomAD3 genomes AF: 0.00379 AC: 577 AN: 152226 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0212

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00400

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00354 AC: 866 AN: 244400 AF XY: 0.00356

Gnomad AFR exome AF: 0.000457

Gnomad AMR exome AF: 0.00192

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0164

Gnomad NFE exome AF: 0.00384

Gnomad OTH exome AF: 0.00467

GnomAD4 exome AF: 0.00361 AC: 5268 AN: 1459054 Hom.: 18 Cov.: 32 AF XY: 0.00354 AC XY: 2573 AN XY: 726014

African (AFR) AF: 0.000508 AC: 17 AN: 33466

American (AMR) AF: 0.00192 AC: 86 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26122

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39692

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86192

European-Finnish (FIN) AF: 0.0145 AC: 742 AN: 51060

Middle Eastern (MID) AF: 0.000530 AC: 3 AN: 5658

European-Non Finnish (NFE) AF: 0.00377 AC: 4195 AN: 1111858

Other (OTH) AF: 0.00293 AC: 177 AN: 60312

GnomAD4 genome AF: 0.00378 AC: 576 AN: 152344 Hom.: 5 Cov.: 33 AF XY: 0.00439 AC XY: 327 AN XY: 74494

African (AFR) AF: 0.000481 AC: 20 AN: 41588

American (AMR) AF: 0.00281 AC: 43 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.0212 AC: 225 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00398 AC: 271 AN: 68012

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00287 Hom.: 0

Bravo AF: 0.00233

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 01, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.6
DANN	Benign	0.84
PhyloP100		-0.76
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs145499943; hg19: chr22-38106399;