rs200793989

chr22-37769297-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_001039141.3(TRIOBP):c.6771G>A(p.Gln2257=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000883 in 1,612,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (0 hom.)
• Consequence: TRIOBP NM_001039141.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.495

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 22-37769297-G-A is Benign according to our data. Variant chr22-37769297-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228042.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}. Variant chr22-37769297-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.495 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.6771G>A	p.Gln2257=	synonymous_variant	21/24	ENST00000644935.1
TRIOBP	NM_007032.5	c.1632G>A	p.Gln544=	synonymous_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.6771G>A	p.Gln2257=	synonymous_variant	21/24		NM_001039141.3	A2
TRIOBP	ENST00000403663.6	c.1632G>A	p.Gln544=	synonymous_variant	11/14	1		P2
TRIOBP	ENST00000344404.10	c.*6254G>A		3_prime_UTR_variant, NMD_transcript_variant	19/22	2

Frequencies

GnomAD3 genomes AF: 0.000525 AC: 80 AN: 152276 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000521 AC: 127 AN: 243814 Hom.: 0 AF XY: 0.000503 AC XY: 67 AN XY: 133112

Gnomad AFR exome AF: 0.000269

Gnomad AMR exome AF: 0.000496

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000933

Gnomad OTH exome AF: 0.000507

GnomAD4 exome AF: 0.000921 AC: 1344 AN: 1459632 Hom.: 0 Cov.: 33 AF XY: 0.000906 AC XY: 658 AN XY: 726074

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000471

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00116

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000518 AC: 79 AN: 152394 Hom.: 0 Cov.: 32 AF XY: 0.000496 AC XY: 37 AN XY: 74524

Gnomad4 AFR AF: 0.000264

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000803 Hom.: 0

Bravo AF: 0.000533

EpiCase AF: 0.00104

EpiControl AF: 0.000952

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2023	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 28, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 22, 2015

p.Gln2257Gln in Exon 21 of TRIOBP: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wi thin the splice consensus sequence, and has been identified in 0.1% (55/53588) o f European chromosomes by the Exome Aggregation Consortium (http://exac.broadins titute.org/; dbSNP rs200793989). -

TRIOBP-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	1.3
Dann	Benign	0.89

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs200793989; hg19: chr22-38165304;