rs199640717

chr22-37734669-A-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.4333A>G(p.Arg1445Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,601,028 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (12 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.17

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=0.003223449).
• BP6: Variant 22-37734669-A-G is Benign according to our data. Variant chr22-37734669-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 43857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37734669-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00215 (327/152206) while in subpopulation AMR AF= 0.00425 (65/15296). AF 95% confidence interval is 0.00342. There are 1 homozygotes in gnomad4. There are 156 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.4333A>G	p.Arg1445Gly	missense_variant	9/24	ENST00000644935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.4333A>G	p.Arg1445Gly	missense_variant	9/24		NM_001039141.3	A2
TRIOBP	ENST00000344404.10	c.*3816A>G		3_prime_UTR_variant, NMD_transcript_variant	7/22	2

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 327 AN: 152088 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00296

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00175 AC: 382 AN: 217794 Hom.: 2 AF XY: 0.00177 AC XY: 213 AN XY: 120034

Gnomad AFR exome AF: 0.000743

Gnomad AMR exome AF: 0.00242

Gnomad ASJ exome AF: 0.00172

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000350

Gnomad FIN exome AF: 0.000158

Gnomad NFE exome AF: 0.00280

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00311 AC: 4511 AN: 1448822 Hom.: 12 Cov.: 36 AF XY: 0.00306 AC XY: 2201 AN XY: 719724

Gnomad4 AFR exome AF: 0.000661

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.00182

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000236

Gnomad4 FIN exome AF: 0.0000779

Gnomad4 NFE exome AF: 0.00377

Gnomad4 OTH exome AF: 0.00281

GnomAD4 genome AF: 0.00215 AC: 327 AN: 152206 Hom.: 1 Cov.: 33 AF XY: 0.00210 AC XY: 156 AN XY: 74416

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00296

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00307 Hom.: 3

Bravo AF: 0.00234

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000279 AC: 1

ESP6500EA AF: 0.00164 AC: 13

ExAC AF: 0.00141 AC: 168

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 14, 2015

p.Arg1445Gly in exon 9 of TRIOBP: This variant is not expected to have clinical significance because it is has been identified in 0.4% (122/27370) of European c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs199640717). -

TRIOBP-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	18
Dann	Benign	0.90
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.44	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Benign	0.11
Sift	Uncertain	0.0020	D;.
Sift4G	Benign	0.24	T;.
Polyphen		0.0060	B;B
Vest4		0.31
MVP		0.30
MPC		0.18
ClinPred		0.028	T
GERP RS		4.6
Varity_R		0.12
gMVP		0.19

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199640717; hg19: chr22-38130676;