rs202059880

Positions:

• chr22-37734475-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_001039141.3(TRIOBP):​c.4139A>G​(p.Glu1380Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,612,726 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000094 (0 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.13

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 -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.005646318).
• BP6: Variant 22-37734475-A-G is Benign according to our data. Variant chr22-37734475-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 178555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37734475-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00118 (180/152252) while in subpopulation AFR AF= 0.00424 (176/41554). AF 95% confidence interval is 0.00372. There are 1 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.4139A>G	p.Glu1380Gly	missense_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.4139A>G	p.Glu1380Gly	missense_variant	9/24		NM_001039141.3	ENSP00000496394.1
TRIOBP	ENST00000344404.10	n.*3622A>G		non_coding_transcript_exon_variant	7/22	2		ENSP00000340312.6
TRIOBP	ENST00000344404.10	n.*3622A>G		3_prime_UTR_variant	7/22	2		ENSP00000340312.6

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 180 AN: 152134 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000280 AC: 69 AN: 246434 Hom.: 0 AF XY: 0.000223 AC XY: 30 AN XY: 134338

Gnomad AFR exome AF: 0.00429

Gnomad AMR exome AF: 0.0000582

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: 0.00000899

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000945 AC: 138 AN: 1460474 Hom.: 0 Cov.: 36 AF XY: 0.0000964 AC XY: 70 AN XY: 726482

Gnomad4 AFR exome AF: 0.00338

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.00118 AC: 180 AN: 152252 Hom.: 1 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74450

Gnomad4 AFR AF: 0.00424

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.00139

ESP6500AA AF: 0.00313 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000306 AC: 37

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2022	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 21, 2015	p.Glu1380Gly in exon 9 of TRIOBP: This variant is not expected to have clinical significance because it has been identified in 0.4% (36/8730) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs202059880). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2016	- -

TRIOBP-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 05, 2020

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
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.36	.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N;.
REVEL	Benign	0.085
Sift	Uncertain	0.0020	D;.
Sift4G	Benign	0.10	T;.
Polyphen		0.80	P;P
Vest4		0.17
MVP		0.37
MPC		0.17
ClinPred		0.033	T
GERP RS		5.6
Varity_R		0.089
gMVP		0.13

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs202059880; hg19: chr22-38130482;