rs397517814
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4
The NM_133379.5(TTN):βc.15280_15312delβ(p.Thr5102_Glu5112del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000014 in 142,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β ). Synonymous variant affecting the same amino acid position (i.e. R5094R) has been classified as Likely benign.
Frequency
Genomes: π 0.000014 ( 0 hom., cov: 32)
Exomes π: 0.000027 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TTN
NM_133379.5 inframe_deletion
NM_133379.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.71
Genes affected
TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_133379.5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_133379.5 | c.15280_15312del | p.Thr5102_Glu5112del | inframe_deletion | 46/46 | ENST00000360870.10 | |
TTN | NM_001267550.2 | c.11312-5199_11312-5167del | intron_variant | ENST00000589042.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000360870.10 | c.15280_15312del | p.Thr5102_Glu5112del | inframe_deletion | 46/46 | 5 | NM_133379.5 | ||
TTN | ENST00000589042.5 | c.11312-5199_11312-5167del | intron_variant | 5 | NM_001267550.2 | P1 | |||
TTN-AS1 | ENST00000659121.1 | n.1223+4121_1223+4153del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000140 AC: 2AN: 142668Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000241 AC: 6AN: 249252Hom.: 0 AF XY: 0.0000371 AC XY: 5AN XY: 134850
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000269 AC: 39AN: 1451828Hom.: 0 AF XY: 0.0000304 AC XY: 22AN XY: 722594
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GnomAD4 genome ? AF: 0.0000140 AC: 2AN: 142784Hom.: 0 Cov.: 32 AF XY: 0.0000287 AC XY: 2AN XY: 69796
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
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 | Feb 22, 2013 | The Thr5102_Glu5112del variant in TTN has not been reported in the literature no r previously identified by our laboratory. The frequency of this variant in larg e European American and African American populations cannot be determined from t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/) because co verage at this position was insufficient or unavailable. Amino acids 5102-5112 a re repeated several times in the last exon of an alternative transcript (?Novex- 3?) and a duplication of the same region has been identified in 1.1% (4/374) of Caucasian control chromosomes tested by our laboratory, raising the possibility that altering the number of repeat units does not impact the protein. In additio n, the function of the Novex-3 transcript is unclear and thus additional data is needed to establish the clinical significance of Thr5102_Glu5112del variant. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at