22-37735388-G-T

Position:

• chr22-37735388-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001039141.3(TRIOBP):​c.5052G>T​(p.Thr1684Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00761 in 1,603,936 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0077 (51 hom.)
• Consequence: TRIOBP NM_001039141.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.322

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 22-37735388-G-T is Benign according to our data. Variant chr22-37735388-G-T is described in ClinVar as [Benign]. Clinvar id is 43858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.322 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00638 (972/152314) while in subpopulation AMR AF= 0.00921 (141/15308). AF 95% confidence interval is 0.00803. There are 3 homozygotes in gnomad4. There are 442 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.5052G>T	p.Thr1684Thr	synonymous_variant	9/24	ENST00000644935.1	NP_001034230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.5052G>T	p.Thr1684Thr	synonymous_variant	9/24		NM_001039141.3	ENSP00000496394.1
TRIOBP	ENST00000344404.10	n.*4535G>T		non_coding_transcript_exon_variant	7/22	2		ENSP00000340312.6
TRIOBP	ENST00000344404.10	n.*4535G>T		3_prime_UTR_variant	7/22	2		ENSP00000340312.6

Frequencies

GnomAD3 genomes AF: 0.00639 AC: 973 AN: 152196 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00922

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00862

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00744 AC: 1653 AN: 222120 Hom.: 11 AF XY: 0.00752 AC XY: 915 AN XY: 121740

Gnomad AFR exome AF: 0.00251

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0207

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00207

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00966

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.00774 AC: 11233 AN: 1451622 Hom.: 51 Cov.: 36 AF XY: 0.00785 AC XY: 5660 AN XY: 721432

Gnomad4 AFR exome AF: 0.00301

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.0194

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00265

Gnomad4 FIN exome AF: 0.00224

Gnomad4 NFE exome AF: 0.00830

Gnomad4 OTH exome AF: 0.00947

GnomAD4 genome AF: 0.00638 AC: 972 AN: 152314 Hom.: 3 Cov.: 33 AF XY: 0.00593 AC XY: 442 AN XY: 74480

Gnomad4 AFR AF: 0.00243

Gnomad4 AMR AF: 0.00921

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00860

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00807 Hom.: 7

Bravo AF: 0.00737

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	TRIOBP: BP4, BP7, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Thr1684Thr in Exon 09 of TRIOBP: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 1.0% (67/6622) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs41283241). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.19
DANN	Benign	0.65

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs41283241; hg19: chr22-38131395;