rs1553713878
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM4PP3
The NM_001267550.2(TTN):βc.46521_46601delβ(p.Lys15507_His15534delinsAsn) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,446 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.0000021 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TTN
NM_001267550.2 inframe_deletion
NM_001267550.2 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.86
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 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_001267550.2.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.46521_46601del | p.Lys15507_His15534delinsAsn | inframe_deletion | 250/363 | ENST00000589042.5 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.46521_46601del | p.Lys15507_His15534delinsAsn | inframe_deletion | 250/363 | 5 | NM_001267550.2 | P1 | |
| TTN-AS1 | ENST00000659121.1 | n.502+22036_502+22116del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes 0.00 AC: 1AN: 151806Hom.: 0 Cov.: 32 FAILED QC
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460446Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726522
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GnomAD4 genome 0.00000659 AC: 1AN: 151806Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74108
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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 | Sep 10, 2012 | Variant classified as Uncertain Significance - Favor Pathogenic. The Lys12939_Hi s12966delinsAsn variant in TTN has not been reported in the literature nor previ ously identified by our laboratory. This variant deletes 28 amino acid residues from lysine (Lys) at position 12939 to histidine (His) at position 12966 and ins erts an asparagine (Asn), but does not alter the protein reading frame. While th is variant results in the loss of a section of the protein, it is unclear how th is variant may impact the protein. Additional studies are needed to fully assess the clinical significance of this variant. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 02, 2021 | The c.19326_19406del81 variant (also known as p.K6442_H6469delinsN), located in coding exon 77 of the TTN gene, results from an in-frame deletion of 81 nucleotides at nucleotide positions 19326 to 19406. This results in an in-frame deletion of 28 amino acids and insertion of an asparagine residue. This amino acid region is well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at