rs144634857

Positions:

• chr22-37713346-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001039141.3(TRIOBP):​c.391G>A​(p.Gly131Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,613,934 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (38 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.333

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]

ENSG00000100101 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030972362).
• BP6: Variant 22-37713346-G-A is Benign according to our data. Variant chr22-37713346-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 43850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37713346-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00456 (694/152242) while in subpopulation AMR AF= 0.00707 (108/15270). AF 95% confidence interval is 0.00599. There are 5 homozygotes in gnomad4. There are 337 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.391G>A	p.Gly131Ser	missense_variant	5/24	ENST00000644935.1	NP_001034230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.391G>A	p.Gly131Ser	missense_variant	5/24		NM_001039141.3	ENSP00000496394.1
ENSG00000100101	ENST00000455236.4	n.*727G>A		non_coding_transcript_exon_variant	11/13	5		ENSP00000477208.1
ENSG00000100101	ENST00000455236.4	n.*727G>A		3_prime_UTR_variant	11/13	5		ENSP00000477208.1

Frequencies

GnomAD3 genomes AF: 0.00456 AC: 693 AN: 152124 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.00708

Gnomad ASJ AF: 0.0254

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00553

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00502 AC: 1252 AN: 249182 Hom.: 9 AF XY: 0.00517 AC XY: 699 AN XY: 135216

Gnomad AFR exome AF: 0.000775

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.0294

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.000233

Gnomad NFE exome AF: 0.00632

Gnomad OTH exome AF: 0.00677

GnomAD4 exome AF: 0.00516 AC: 7543 AN: 1461692 Hom.: 38 Cov.: 32 AF XY: 0.00525 AC XY: 3821 AN XY: 727148

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00344

Gnomad4 ASJ exome AF: 0.0277

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00245

Gnomad4 FIN exome AF: 0.000338

Gnomad4 NFE exome AF: 0.00526

Gnomad4 OTH exome AF: 0.00614

GnomAD4 genome AF: 0.00456 AC: 694 AN: 152242 Hom.: 5 Cov.: 32 AF XY: 0.00453 AC XY: 337 AN XY: 74436

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00707

Gnomad4 ASJ AF: 0.0254

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00553

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00698 Hom.: 8

Bravo AF: 0.00499

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000939 AC: 4

ESP6500EA AF: 0.00693 AC: 59

ExAC AF: 0.00465 AC: 563

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00692

EpiControl AF: 0.00800

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	TRIOBP: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 31, 2018	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Gly131Ser in Exon 05 of TRIOBP: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (47/6930) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs144634857). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 31, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.3
DANN	Benign	0.88
DEOGEN2	Benign	0.011	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0090	N
LIST_S2	Benign	0.32	.;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.21	N;.
REVEL	Benign	0.052
Sift	Benign	0.42	T;.
Sift4G	Benign	0.74	T;.
Polyphen		0.066	B;B
Vest4		0.14
MVP		0.14
MPC		0.12
ClinPred		0.00037	T
GERP RS		-4.6
Varity_R		0.014
gMVP		0.064

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs144634857; hg19: chr22-38109353;