rs182816010

chr22-37734439-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_001039141.3(TRIOBP):c.4103G>A(p.Arg1368Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,613,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1368W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.750

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009719998).
• BP6: Variant 22-37734439-G-A is Benign according to our data. Variant chr22-37734439-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 504688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.4103G>A	p.Arg1368Gln	missense_variant	9/24	ENST00000644935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.4103G>A	p.Arg1368Gln	missense_variant	9/24		NM_001039141.3	A2
TRIOBP	ENST00000344404.10	c.*3586G>A		3_prime_UTR_variant, NMD_transcript_variant	7/22	2

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000158 AC: 39 AN: 247292 Hom.: 1 AF XY: 0.000104 AC XY: 14 AN XY: 134720

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000279

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000637 AC: 93 AN: 1460984 Hom.: 0 Cov.: 57 AF XY: 0.0000550 AC XY: 40 AN XY: 726776

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000554

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74454

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000193 Hom.: 0

Bravo AF: 0.000499

ESP6500AA AF: 0.00154 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000141 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Sep 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	TRIOBP: BP4 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 21, 2016

p.Arg1368Gln in exon 9 of TRIOBP: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, >5 mammals have a glutamine (Gln) at this position despite high nearby am ino acid conservation. In addition, computational prediction tools do not sugges t a high likelihood of impact to the protein. It has been identified in 0.1% (9/ 9264) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs182816010). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	11
Dann	Benign	0.95
DEOGEN2	Benign	0.028	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.025	N
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.0097	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.64	N;.
REVEL	Benign	0.0090
Sift	Benign	0.34	T;.
Sift4G	Benign	0.30	T;.
Polyphen		0.12	B;B
Vest4		0.058
MVP		0.23
MPC		0.13
ClinPred		0.0052	T
GERP RS		-0.16
Varity_R		0.022
gMVP		0.092

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs182816010; hg19: chr22-38130446;