NM_001039141.3:c.115-74G>A

Variant names:

• chr22-37710353-G-A
• rs115587759
• NM_001039141.3:c.115-74G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001039141.3(TRIOBP):​c.115-74G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,599,626 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0082 (17 hom., cov: 33)
  • Exomes 𝑓: 0.00095 (26 hom.)
• Consequence: TRIOBP NM_001039141.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.590
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 22-37710353-G-A is Benign according to our data. Variant chr22-37710353-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1212232.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00817 (1245/152332) while in subpopulation AFR AF = 0.0282 (1173/41580). AF 95% confidence interval is 0.0269. There are 17 homozygotes in GnomAd4. There are 583 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.115-74G>A		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.115-74G>A		intron_variant	Intron 3 of 23		NM_001039141.3	ENSP00000496394.1
ENSG00000100101	ENST00000455236.4	n.*451-74G>A		intron_variant	Intron 9 of 12	5		ENSP00000477208.1
TRIOBP	ENST00000492485.5	n.251-74G>A		intron_variant	Intron 2 of 4	1
TRIOBP	ENST00000344404.10	n.115-74G>A		intron_variant	Intron 2 of 21	2		ENSP00000340312.6

Frequencies

GnomAD3 genomes AF: 0.00803 AC: 1222 AN: 152214 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

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: 0.000279

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.000948 AC: 1372 AN: 1447294 Hom.: 26 AF XY: 0.000880 AC XY: 634 AN XY: 720228

African (AFR) AF: 0.0274 AC: 913 AN: 33284

American (AMR) AF: 0.00190 AC: 84 AN: 44274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39430

South Asian (SAS) AF: 0.000129 AC: 11 AN: 85468

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45588

Middle Eastern (MID) AF: 0.000772 AC: 4 AN: 5184

European-Non Finnish (NFE) AF: 0.000157 AC: 174 AN: 1108088

Other (OTH) AF: 0.00308 AC: 185 AN: 59992

GnomAD4 genome AF: 0.00817 AC: 1245 AN: 152332 Hom.: 17 Cov.: 33 AF XY: 0.00783 AC XY: 583 AN XY: 74480

African (AFR) AF: 0.0282 AC: 1173 AN: 41580

American (AMR) AF: 0.00300 AC: 46 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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: 0.000279 AC: 19 AN: 68012

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00621 Hom.: 2

Bravo AF: 0.00893

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 24, 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	-0.61
CADD	Benign	17
DANN	Benign	0.82
PhyloP100		0.59
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: rs115587759; hg19: chr22-38106360;