rs749541061
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_015311.3(OBSL1):c.2980C>T(p.Arg994Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,704 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R994H) has been classified as Benign.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 1 hom. )
Consequence
OBSL1
NM_015311.3 missense
NM_015311.3 missense
Scores
1
10
8
Clinical Significance
Conservation
PhyloP100: 3.87
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 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 |
---|---|---|---|---|---|---|---|
OBSL1 | NM_015311.3 | c.2980C>T | p.Arg994Cys | missense_variant | 9/21 | ENST00000404537.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OBSL1 | ENST00000404537.6 | c.2980C>T | p.Arg994Cys | missense_variant | 9/21 | 1 | NM_015311.3 | P1 | |
ENST00000597192.1 | n.389G>A | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000442 AC: 11AN: 248724Hom.: 0 AF XY: 0.0000741 AC XY: 10AN XY: 134876
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GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461608Hom.: 1 Cov.: 31 AF XY: 0.0000316 AC XY: 23AN XY: 727078
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74314
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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 | Invitae | May 15, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 994 of the OBSL1 protein (p.Arg994Cys). This variant is present in population databases (rs749541061, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of 3M syndrome (PMID: 30755392). ClinVar contains an entry for this variant (Variation ID: 598981). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Benign
T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;L
MutationTaster
Benign
D;D;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;.
REVEL
Uncertain
Sift
Uncertain
D;D;.
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MutPred
Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
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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