NM_001039141.3:c.115-55G>T

Variant names:

• chr22-37710372-G-T
• rs73409461
• NM_001039141.3:c.115-55G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001039141.3(TRIOBP):​c.115-55G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000672 in 1,608,070 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (7 hom.)
• Consequence: TRIOBP NM_001039141.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.303
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 22-37710372-G-T is Benign according to our data. Variant chr22-37710372-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1220422.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00339 (516/152346) while in subpopulation AFR AF = 0.0119 (493/41586). AF 95% confidence interval is 0.011. There are 3 homozygotes in GnomAd4. There are 233 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.115-55G>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.115-55G>T		intron_variant	Intron 3 of 23		NM_001039141.3	ENSP00000496394.1
ENSG00000100101	ENST00000455236.4	n.*451-55G>T		intron_variant	Intron 9 of 12	5		ENSP00000477208.1
TRIOBP	ENST00000492485.5	n.251-55G>T		intron_variant	Intron 2 of 4	1
TRIOBP	ENST00000344404.10	n.115-55G>T		intron_variant	Intron 2 of 21	2		ENSP00000340312.6

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152228 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.000388 AC: 565 AN: 1455724 Hom.: 7 AF XY: 0.000324 AC XY: 235 AN XY: 724316

African (AFR) AF: 0.0143 AC: 479 AN: 33426

American (AMR) AF: 0.000515 AC: 23 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000814 AC: 7 AN: 86022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48760

Middle Eastern (MID) AF: 0.000365 AC: 2 AN: 5472

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111464

Other (OTH) AF: 0.000781 AC: 47 AN: 60214

GnomAD4 genome AF: 0.00339 AC: 516 AN: 152346 Hom.: 3 Cov.: 33 AF XY: 0.00313 AC XY: 233 AN XY: 74496

African (AFR) AF: 0.0119 AC: 493 AN: 41586

American (AMR) AF: 0.000980 AC: 15 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.000277 Hom.: 0

Bravo AF: 0.00394

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 06, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.94
PhyloP100		0.30

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: rs73409461; hg19: chr22-38106379;