22-37765832-G-GC

Variant names:

• chr22-37765832-G-GC
• rs149021782
• NM_001039141.3:c.6472+15_6472+16insC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001039141.3(TRIOBP):​c.6472+15_6472+16insC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00595 in 1,585,328 control chromosomes in the GnomAD database, including 47 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (43 hom.)
• Consequence: TRIOBP NM_001039141.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.07
• Publications: 1 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)
• hearing loss, autosomal recessive

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 22-37765832-G-GC is Benign according to our data. Variant chr22-37765832-G-GC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00447 (676/151322) while in subpopulation AMR AF = 0.00794 (121/15236). AF 95% confidence interval is 0.00679. There are 4 homozygotes in GnomAd4. There are 319 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	NM_001039141.3	MANE Select	c.6472+15_6472+16insC		intron	N/A	NP_001034230.1	Q9H2D6-1
	TRIOBP	NM_007032.5		c.1333+15_1333+16insC		intron	N/A	NP_008963.3	Q9H2D6-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	ENST00000644935.1	MANE Select	c.6472+15_6472+16insC		intron	N/A	ENSP00000496394.1	Q9H2D6-1
	TRIOBP	ENST00000403663.6	TSL:1	c.1333+15_1333+16insC		intron	N/A	ENSP00000386026.2	Q9H2D6-7
	TRIOBP	ENST00000344404.10	TSL:2	n.*5955+15_*5955+16insC		intron	N/A	ENSP00000340312.6	H7BXW4

Frequencies

GnomAD3 genomes AF: 0.00447 AC: 676 AN: 151204 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00795

Gnomad ASJ AF: 0.0151

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000838

Gnomad FIN AF: 0.000474

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00622

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00440 AC: 890 AN: 202474 AF XY: 0.00428

Gnomad AFR exome AF: 0.00165

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000736

Gnomad NFE exome AF: 0.00597

Gnomad OTH exome AF: 0.00714

GnomAD4 exome AF: 0.00611 AC: 8755 AN: 1434006 Hom.: 43 Cov.: 35 AF XY: 0.00601 AC XY: 4279 AN XY: 711668

African (AFR) AF: 0.00121 AC: 40 AN: 33100

American (AMR) AF: 0.00379 AC: 161 AN: 42466

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 364 AN: 25708

East Asian (EAS) AF: 0.00 AC: 0 AN: 38894

South Asian (SAS) AF: 0.00201 AC: 168 AN: 83380

European-Finnish (FIN) AF: 0.000616 AC: 27 AN: 43824

Middle Eastern (MID) AF: 0.00680 AC: 34 AN: 5002

European-Non Finnish (NFE) AF: 0.00690 AC: 7603 AN: 1102208

Other (OTH) AF: 0.00602 AC: 358 AN: 59424

GnomAD4 genome AF: 0.00447 AC: 676 AN: 151322 Hom.: 4 Cov.: 32 AF XY: 0.00431 AC XY: 319 AN XY: 73964

African (AFR) AF: 0.00143 AC: 59 AN: 41342

American (AMR) AF: 0.00794 AC: 121 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.0151 AC: 52 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.000839 AC: 4 AN: 4770

European-Finnish (FIN) AF: 0.000474 AC: 5 AN: 10538

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00622 AC: 420 AN: 67536

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00319 Hom.: 1

Bravo AF: 0.00484

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
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: rs149021782; hg19: chr22-38161839;