rs199646135

chr22-37713220-C-G

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.265C>G(p.Pro89Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,613,514 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (24 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.411

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034452677).
• BP6: Variant 22-37713220-C-G is Benign according to our data. Variant chr22-37713220-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 165582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37713220-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00377 (573/152184) while in subpopulation NFE AF= 0.0061 (415/68002). AF 95% confidence interval is 0.00562. There are 3 homozygotes in gnomad4. There are 240 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.265C>G	p.Pro89Ala	missense_variant	5/24	ENST00000644935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.265C>G	p.Pro89Ala	missense_variant	5/24		NM_001039141.3	A2
TRIOBP	ENST00000492485.5	n.391-2543C>G		intron_variant, non_coding_transcript_variant		1
TRIOBP	ENST00000344404.10	c.255-2543C>G		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 574 AN: 152066 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00610

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00439 AC: 1082 AN: 246418 Hom.: 1 AF XY: 0.00492 AC XY: 659 AN XY: 133954

Gnomad AFR exome AF: 0.000456

Gnomad AMR exome AF: 0.00348

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.00672

Gnomad OTH exome AF: 0.00599

GnomAD4 exome AF: 0.00470 AC: 6871 AN: 1461330 Hom.: 24 Cov.: 32 AF XY: 0.00468 AC XY: 3402 AN XY: 726948

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.00398

Gnomad4 ASJ exome AF: 0.0119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00146

Gnomad4 FIN exome AF: 0.000282

Gnomad4 NFE exome AF: 0.00525

Gnomad4 OTH exome AF: 0.00530

GnomAD4 genome AF: 0.00377 AC: 573 AN: 152184 Hom.: 3 Cov.: 32 AF XY: 0.00323 AC XY: 240 AN XY: 74392

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00413

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00610

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00591 Hom.: 0

Bravo AF: 0.00417

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000529 AC: 2

ESP6500EA AF: 0.00802 AC: 66

ExAC AF: 0.00453 AC: 547

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.0103

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	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	TRIOBP: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2018	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Pro89Ala in Exon 05 of TRIOBP: This variant is not expected to have clinical sig nificance because it has been identified in 0.8% (54/6636) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS). -

Autosomal recessive nonsyndromic hearing loss 28 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	15
Dann	Benign	0.92
DEOGEN2	Benign	0.039	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.12	N
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.041
Sift	Benign	0.041	D;.
Sift4G	Benign	0.59	T;.
Polyphen		0.020	B;B
Vest4		0.14
MVP		0.21
MPC		0.12
ClinPred		0.0029	T
GERP RS		-0.52
Varity_R		0.032
gMVP		0.069

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: rs199646135; hg19: chr22-38109227; COSMIC: COSV60381432;