rs138139146

chr22-37769262-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_001039141.3(TRIOBP):c.6736G>A(p.Glu2246Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00695 in 1,609,952 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (47 hom.)
• Consequence: TRIOBP NM_001039141.3 missense, splice_region
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.65

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 -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 22-37769262-G-A is Benign according to our data. Variant chr22-37769262-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 165614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00472 (719/152374) while in subpopulation NFE AF= 0.007 (476/68028). AF 95% confidence interval is 0.00648. There are 5 homozygotes in gnomad4. There are 344 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.6736G>A	p.Glu2246Lys	missense_variant, splice_region_variant	21/24	ENST00000644935.1
TRIOBP	NM_007032.5	c.1597G>A	p.Glu533Lys	missense_variant, splice_region_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.6736G>A	p.Glu2246Lys	missense_variant, splice_region_variant	21/24		NM_001039141.3	A2
TRIOBP	ENST00000403663.6	c.1597G>A	p.Glu533Lys	missense_variant, splice_region_variant	11/14	1		P2
TRIOBP	ENST00000344404.10	c.*6219G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	19/22	2

Frequencies

GnomAD3 genomes AF: 0.00472 AC: 719 AN: 152256 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00700

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00532 AC: 1273 AN: 239260 Hom.: 3 AF XY: 0.00526 AC XY: 688 AN XY: 130708

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.00492

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000873

Gnomad FIN exome AF: 0.00214

Gnomad NFE exome AF: 0.00765

Gnomad OTH exome AF: 0.00770

GnomAD4 exome AF: 0.00719 AC: 10478 AN: 1457578 Hom.: 47 Cov.: 33 AF XY: 0.00699 AC XY: 5067 AN XY: 724886

Gnomad4 AFR exome AF: 0.00141

Gnomad4 AMR exome AF: 0.00545

Gnomad4 ASJ exome AF: 0.0162

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000981

Gnomad4 FIN exome AF: 0.00171

Gnomad4 NFE exome AF: 0.00820

Gnomad4 OTH exome AF: 0.00733

GnomAD4 genome AF: 0.00472 AC: 719 AN: 152374 Hom.: 5 Cov.: 32 AF XY: 0.00462 AC XY: 344 AN XY: 74510

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00700

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00715 Hom.: 2

Bravo AF: 0.00524

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00173 AC: 7

ESP6500EA AF: 0.00564 AC: 47

ExAC AF: 0.00490 AC: 592

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Glu2246Lys in Exon 21 of TRIOBP: This variant is not expected to have clinical s ignificance because it has been identified in 0.5% (37/6742) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs138139146). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 09, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 17, 2015	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2018	This variant is associated with the following publications: (PMID: 26969326, 28089734, 29197352) -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 18, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0071	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.0050	D;.;D
Polyphen		1.0	D;D;.
Vest4		0.84
MVP		0.55
MPC		0.58
ClinPred		0.017	T
GERP RS		4.4
Varity_R		0.37
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs138139146; hg19: chr22-38165269; COSMIC: COSV60374094;