rs28450766

chr22-37734514-C-T

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.4178C>T(p.Pro1393Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,606,316 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (20 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.56

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=0.0030569732).
• BP6: Variant 22-37734514-C-T is Benign according to our data. Variant chr22-37734514-C-T is described in ClinVar as [Benign]. Clinvar id is 43856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37734514-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00681 (1036/152228) while in subpopulation AFR AF= 0.0232 (964/41536). AF 95% confidence interval is 0.022. There are 13 homozygotes in gnomad4. There are 506 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.4178C>T	p.Pro1393Leu	missense_variant	9/24	ENST00000644935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.4178C>T	p.Pro1393Leu	missense_variant	9/24		NM_001039141.3	A2
TRIOBP	ENST00000344404.10	c.*3661C>T		3_prime_UTR_variant, NMD_transcript_variant	7/22	2

Frequencies

GnomAD3 genomes AF: 0.00676 AC: 1029 AN: 152110 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00162 AC: 373 AN: 230630 Hom.: 3 AF XY: 0.00124 AC XY: 157 AN XY: 126340

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000344

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000682

Gnomad OTH exome AF: 0.000710

GnomAD4 exome AF: 0.000754 AC: 1096 AN: 1454088 Hom.: 20 Cov.: 36 AF XY: 0.000627 AC XY: 453 AN XY: 722802

Gnomad4 AFR exome AF: 0.0244

Gnomad4 AMR exome AF: 0.00158

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000106

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000514

Gnomad4 OTH exome AF: 0.00226

GnomAD4 genome AF: 0.00681 AC: 1036 AN: 152228 Hom.: 13 Cov.: 32 AF XY: 0.00680 AC XY: 506 AN XY: 74418

Gnomad4 AFR AF: 0.0232

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00226 Hom.: 3

Bravo AF: 0.00761

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0195 AC: 73

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00179 AC: 216

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Pro1393Leu in Exon 09 of TRIOBP: This variant is not expected to have clinical s ignificance because it has been identified in 1.7% (53/3054) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs28450766). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	15
Dann	Benign	0.86
DEOGEN2	Benign	0.094	T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.088	N
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.7	N;.
REVEL	Benign	0.12
Sift	Benign	0.059	T;.
Sift4G	Benign	0.064	T;.
Polyphen		0.0010	B;B
Vest4		0.054
MVP		0.26
MPC		0.12
ClinPred		0.0073	T
GERP RS		4.5
Varity_R		0.028
gMVP		0.11

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs28450766; hg19: chr22-38130521;