22-37757689-C-T

Position:

• chr22-37757689-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.5764C>T​(p.Arg1922Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000544 in 1,585,132 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (8 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.05

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=0.0034099817).
• BP6: Variant 22-37757689-C-T is Benign according to our data. Variant chr22-37757689-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37757689-C-T is described in Lovd as [Benign]. Variant chr22-37757689-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000414 (63/152304) while in subpopulation EAS AF= 0.00945 (49/5184). AF 95% confidence interval is 0.00735. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.5764C>T	p.Arg1922Trp	missense_variant	16/24	ENST00000644935.1	NP_001034230.1
TRIOBP	NM_007032.5	c.625C>T	p.Arg209Trp	missense_variant	6/14		NP_008963.3
TRIOBP	NM_138632.2	c.625C>T	p.Arg209Trp	missense_variant	6/8		NP_619538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.5764C>T	p.Arg1922Trp	missense_variant	16/24		NM_001039141.3	ENSP00000496394.1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00943

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00118 AC: 232 AN: 195950 Hom.: 2 AF XY: 0.00109 AC XY: 116 AN XY: 106030

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0137

Gnomad SAS exome AF: 0.000463

Gnomad FIN exome AF: 0.0000619

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000558 AC: 800 AN: 1432828 Hom.: 8 Cov.: 32 AF XY: 0.000559 AC XY: 397 AN XY: 710206

Gnomad4 AFR exome AF: 0.0000608

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0158

Gnomad4 SAS exome AF: 0.000413

Gnomad4 FIN exome AF: 0.0000202

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.000354

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74466

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00945

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.000563

ExAC AF: 0.000808 AC: 97

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T;T;.;.;.;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	.;D;.;D;D;D;D
MetaRNN	Benign	0.0034	T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	M;M;.;.;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.4	D;.;D;D;.;D;D
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D;.;D;D;.;D;D
Sift4G	Uncertain	0.0020	D;.;D;D;.;D;D
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.50
MVP		0.66
MPC		0.57
ClinPred		0.15	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.35

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: rs183941928; hg19: chr22-38153696; COSMIC: COSV58525689; COSMIC: COSV58525689;