2-219558345-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_015311.3(OBSL1):c.3341G>A(p.Trp1114Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,612,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000038 ( 0 hom. )
Consequence
OBSL1
NM_015311.3 stop_gained
NM_015311.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.85
Genes affected
OBSL1 (HGNC:29092): (obscurin like cytoskeletal adaptor 1) Cytoskeletal adaptor proteins function in linking the internal cytoskeleton of cells to the cell membrane. This gene encodes a cytoskeletal adaptor protein, which is a member of the Unc-89/obscurin family. The protein contains multiple N- and C-terminal immunoglobulin (Ig)-like domains and a central fibronectin type 3 domain. Mutations in this gene cause 3M syndrome type 2. Alternatively spliced transcript variants encoding different isoforms have been found in this gene. [provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OBSL1 | NM_015311.3 | c.3341G>A | p.Trp1114Ter | stop_gained | 10/21 | ENST00000404537.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OBSL1 | ENST00000404537.6 | c.3341G>A | p.Trp1114Ter | stop_gained | 10/21 | 1 | NM_015311.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152260Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000126 AC: 31AN: 245354Hom.: 0 AF XY: 0.000127 AC XY: 17AN XY: 133608
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GnomAD4 exome AF: 0.0000384 AC: 56AN: 1460164Hom.: 0 Cov.: 35 AF XY: 0.0000454 AC XY: 33AN XY: 726362
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152378Hom.: 0 Cov.: 34 AF XY: 0.0000268 AC XY: 2AN XY: 74522
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Coarctation of aorta;C0018794:Heart block;C0018817:Atrial septal defect;C0018818:Ventricular septal defect;C0152415:Ankyloglossia;C0264353:Bronchomalacia;C0432123:Sagittal craniosynostosis;C1837658:Delayed gross motor development;C1850049:Clinodactyly of the 5th finger;C1858120:Generalized hypotonia;C1862095:Bilateral single transverse palmar creases;C4021164:Bicoronal synostosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Personalized Medicine, Children's Hospital Los Angeles | - | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Feb 22, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;D
Vest4
ClinPred
T
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at