rs200850285
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_001039141.3(TRIOBP):c.7010G>A(p.Arg2337Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000545 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000056 ( 0 hom. )
Consequence
TRIOBP
NM_001039141.3 missense
NM_001039141.3 missense
Scores
3
15
Clinical Significance
Conservation
PhyloP100: 5.55
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.02940765).
BP6
?
Variant 22-37772674-G-A is Benign according to our data. Variant chr22-37772674-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505078.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRIOBP | NM_001039141.3 | c.7010G>A | p.Arg2337Gln | missense_variant | 23/24 | ENST00000644935.1 | |
TRIOBP | NM_007032.5 | c.1871G>A | p.Arg624Gln | missense_variant | 13/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRIOBP | ENST00000644935.1 | c.7010G>A | p.Arg2337Gln | missense_variant | 23/24 | NM_001039141.3 | A2 | ||
TRIOBP | ENST00000403663.6 | c.1871G>A | p.Arg624Gln | missense_variant | 13/14 | 1 | P2 | ||
TRIOBP | ENST00000344404.10 | c.*6493G>A | 3_prime_UTR_variant, NMD_transcript_variant | 21/22 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000108 AC: 27AN: 249472Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135354
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GnomAD4 exome AF: 0.0000561 AC: 82AN: 1461832Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 49AN XY: 727212
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74352
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 18, 2022 | ClinVar contains an entry for this variant (Variation ID: 505078). This variant has not been reported in the literature in individuals affected with TRIOBP-related conditions. This variant is present in population databases (rs200850285, gnomAD 0.2%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2337 of the TRIOBP protein (p.Arg2337Gln). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The TRIOBP p.Arg624Gln variant was identified in dbSNP (ID: rs200850285), ClinVar (classified as likely benign by Laboratory for Molecular Medicine) and LOVD 3.0 (classified as a VUS) but was not identified in the literature. The variant was identified in control databases in 27 of 249472 chromosomes at a frequency of 0.000108 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 21 of 10070 chromosomes (freq: 0.002085), Other in 2 of 6066 chromosomes (freq: 0.00033), South Asian in 1 of 30600 chromosomes (freq: 0.000033), Latino in 1 of 34520 chromosomes (freq: 0.000029) and European (non-Finnish) in 2 of 113246 chromosomes (freq: 0.000018), but was not observed in the African, East Asian, or European (Finnish) populations. The p.Arg624 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 02, 2016 | p.Arg2337Gln in exon 23 of TRIOBP: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, 6 mammals have a Glutamine (Gln) at this position despite high nearby am ino acid conservation. It has been identified in 6/66534 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs200850285). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.;N
REVEL
Benign
Sift
Benign
T;.;T
Sift4G
Benign
T;.;T
Polyphen
B;B;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0306);Loss of MoRF binding (P = 0.0306);.;
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at