rs878854304
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_001267550.2(TTN):c.4060_4062delGTT(p.Val1354del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,178 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
TTN
NM_001267550.2 conservative_inframe_deletion
NM_001267550.2 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.28
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 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_001267550.2. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.4060_4062delGTT | p.Val1354del | conservative_inframe_deletion | 24/363 | ENST00000589042.5 | NP_001254479.2 | |
| TTN | NM_133379.5 | c.4060_4062delGTT | p.Val1354del | conservative_inframe_deletion | 24/46 | ENST00000360870.10 | NP_596870.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.4060_4062delGTT | p.Val1354del | conservative_inframe_deletion | 24/363 | 5 | NM_001267550.2 | ENSP00000467141.1 | ||
| TTN | ENST00000360870.10 | c.4060_4062delGTT | p.Val1354del | conservative_inframe_deletion | 24/46 | 5 | NM_133379.5 | ENSP00000354117.4 |
Frequencies
GnomAD3 genomes 0.00000660 AC: 1AN: 151440Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250640Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135414
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461738Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727178
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GnomAD4 genome 0.00000660 AC: 1AN: 151440Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 73960
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 22, 2015 | - - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 14, 2021 | - - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 23, 2021 | - - |
Computational scores
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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