rs147273930

chr22-37751827-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM2 PP3 BP6_Very_Strong BS1

The NM_001039141.3(TRIOBP):c.5378A>C(p.Glu1793Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000223 in 1,599,480 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: TRIOBP NM_001039141.3 missense, splice_region
• Scores: Splicing: ADA: 0.9905
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.85

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 -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 22-37751827-A-C is Benign according to our data. Variant chr22-37751827-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 228035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37751827-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00122 (182/149676) while in subpopulation AFR AF= 0.00439 (178/40532). AF 95% confidence interval is 0.00386. There are 0 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	UniProt
TRIOBP	NM_001039141.3	c.5378A>C	p.Glu1793Ala	missense_variant, splice_region_variant	12/24	ENST00000644935.1
TRIOBP	NM_007032.5	c.239A>C	p.Glu80Ala	missense_variant, splice_region_variant	2/14
TRIOBP	NM_138632.2	c.239A>C	p.Glu80Ala	missense_variant, splice_region_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.5378A>C	p.Glu1793Ala	missense_variant, splice_region_variant	12/24		NM_001039141.3	A2

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 176 AN: 149558 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00426

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000485

GnomAD3 exomes AF: 0.000307 AC: 77 AN: 250986 Hom.: 1 AF XY: 0.000265 AC XY: 36 AN XY: 135768

Gnomad AFR exome AF: 0.00431

Gnomad AMR exome AF: 0.000145

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: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000120 AC: 174 AN: 1449804 Hom.: 1 Cov.: 31 AF XY: 0.000107 AC XY: 77 AN XY: 720892

Gnomad4 AFR exome AF: 0.00425

Gnomad4 AMR exome AF: 0.000136

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.06e-7

Gnomad4 OTH exome AF: 0.000353

GnomAD4 genome AF: 0.00122 AC: 182 AN: 149676 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 85 AN XY: 72944

Gnomad4 AFR AF: 0.00439

Gnomad4 AMR AF: 0.000133

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000211

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.000375 Hom.: 0

Bravo AF: 0.00146

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000387 AC: 47

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 17, 2015	p.Glu1793Ala in exon 12 of TRIOBP: This variant is not expected to have clinical significance because it has been identified in 0.4% (45/10334) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs147273930). -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jul 23, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;.;.;.;D;T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.0060	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.3	L;L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	D;.;D;D;.;D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;.;D;D;.;D;D;D
Sift4G	Uncertain	0.0050	D;.;D;D;.;D;D;D
Polyphen		1.0	D;D;.;.;.;.;.;.
Vest4		0.55
MVP		0.54
MPC		0.57
ClinPred		0.052	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.36
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.89
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: rs147273930; hg19: chr22-38147834;