22-37765828-TGG-TGGGG

Variant names:

• chr22-37765828-T-TGG
• rs3833924
• NM_001039141.3:c.6472+18_6472+19dupGG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_001039141.3(TRIOBP):​c.6472+18_6472+19dupGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000771 in 1,533,302 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00082 (0 hom.)
• Consequence: TRIOBP NM_001039141.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.29
• Publications: 6 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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 22-37765828-T-TGG is Benign according to our data. Variant chr22-37765828-T-TGG is described in ClinVar as Benign. ClinVar VariationId is 1598921.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000278 (42/151288) while in subpopulation SAS AF = 0.00189 (9/4758). AF 95% confidence interval is 0.000986. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039141.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	NM_001039141.3	MANE Select	c.6472+18_6472+19dupGG		intron	N/A	NP_001034230.1
	TRIOBP	NM_007032.5		c.1333+18_1333+19dupGG		intron	N/A	NP_008963.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	ENST00000644935.1	MANE Select	c.6472+11_6472+12insGG		intron	N/A	ENSP00000496394.1
	TRIOBP	ENST00000403663.6	TSL:1	c.1333+11_1333+12insGG		intron	N/A	ENSP00000386026.2
	TRIOBP	ENST00000344404.10	TSL:2	n.*5955+11_*5955+12insGG		intron	N/A	ENSP00000340312.6

Frequencies

GnomAD3 genomes AF: 0.000278 AC: 42 AN: 151170 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00189

Gnomad FIN AF: 0.000572

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000266

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00219 AC: 388 AN: 176912 AF XY: 0.00205

Gnomad AFR exome AF: 0.00291

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.000733

Gnomad EAS exome AF: 0.00142

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.00265

Gnomad OTH exome AF: 0.00191

GnomAD4 exome AF: 0.000825 AC: 1140 AN: 1382014 Hom.: 0 Cov.: 34 AF XY: 0.000934 AC XY: 640 AN XY: 685064

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00154 AC: 48 AN: 31124

American (AMR) AF: 0.000906 AC: 36 AN: 39716

Ashkenazi Jewish (ASJ) AF: 0.000322 AC: 8 AN: 24810

East Asian (EAS) AF: 0.000832 AC: 31 AN: 37272

South Asian (SAS) AF: 0.00197 AC: 159 AN: 80524

European-Finnish (FIN) AF: 0.00214 AC: 88 AN: 41028

Middle Eastern (MID) AF: 0.00189 AC: 9 AN: 4754

European-Non Finnish (NFE) AF: 0.000669 AC: 713 AN: 1065566

Other (OTH) AF: 0.000839 AC: 48 AN: 57220

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000278 AC: 42 AN: 151288 Hom.: 0 Cov.: 0 AF XY: 0.000338 AC XY: 25 AN XY: 73856

African (AFR) AF: 0.000170 AC: 7 AN: 41242

American (AMR) AF: 0.0000658 AC: 1 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5098

South Asian (SAS) AF: 0.00189 AC: 9 AN: 4758

European-Finnish (FIN) AF: 0.000572 AC: 6 AN: 10496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000266 AC: 18 AN: 67744

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00966 Hom.: 2287

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3833924; hg19: chr22-38161835;