rs727503530
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001039141.3(TRIOBP):āc.6961T>Cā(p.Tyr2321His) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,613,954 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000085 ( 1 hom., cov: 32)
Exomes š: 0.0000082 ( 0 hom. )
Consequence
TRIOBP
NM_001039141.3 missense
NM_001039141.3 missense
Scores
2
12
4
Clinical Significance
Conservation
PhyloP100: 5.95
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRIOBP | NM_001039141.3 | c.6961T>C | p.Tyr2321His | missense_variant | 23/24 | ENST00000644935.1 | |
TRIOBP | NM_007032.5 | c.1822T>C | p.Tyr608His | missense_variant | 13/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRIOBP | ENST00000644935.1 | c.6961T>C | p.Tyr2321His | missense_variant | 23/24 | NM_001039141.3 | A2 | ||
TRIOBP | ENST00000403663.6 | c.1822T>C | p.Tyr608His | missense_variant | 13/14 | 1 | P2 | ||
TRIOBP | ENST00000344404.10 | c.*6444T>C | 3_prime_UTR_variant, NMD_transcript_variant | 21/22 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000855 AC: 13AN: 152116Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249444Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135380
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461838Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727216
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GnomAD4 genome ? AF: 0.0000855 AC: 13AN: 152116Hom.: 1 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74306
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 22, 2013 | The Tyr2321His variant in TRIOBP has not been previously reported in individuals with hearing loss or in large population studies. Computational analyses (amino acid biochemical properties, conservation, AlignGVGD, PolyPhen2, SIFT) do not p rovide strong evidence for or against an impact to the protein. In summary, add itional data is needed to assess the clinical significance of this variant. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 2321 of the TRIOBP protein (p.Tyr2321His). This variant is present in population databases (rs727503530, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TRIOBP-related conditions. ClinVar contains an entry for this variant (Variation ID: 165616). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D
REVEL
Uncertain
Sift
Uncertain
D;.;T
Sift4G
Pathogenic
D;.;D
Polyphen
D;D;.
Vest4
MutPred
Gain of disorder (P = 0.0221);Gain of disorder (P = 0.0221);.;
MVP
MPC
ClinPred
D
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