rs377232641
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting
The NM_001267550.2(TTN):c.29454_29456del(p.Glu9820del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000193 in 1,607,524 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
TTN
NM_001267550.2 inframe_deletion
NM_001267550.2 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.14
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]
TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
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 | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.29454_29456del | p.Glu9820del | inframe_deletion | 103/363 | ENST00000589042.5 | |
LOC124906100 | XR_007087318.1 | n.2186-8426_2186-8424del | intron_variant, non_coding_transcript_variant | ||||
LOC124907912 | XR_007087321.1 | n.7315-1879_7315-1877del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.29454_29456del | p.Glu9820del | inframe_deletion | 103/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.503-29176_503-29174del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152116Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000422 AC: 10AN: 236866Hom.: 0 AF XY: 0.0000467 AC XY: 6AN XY: 128446
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GnomAD4 exome AF: 0.00000893 AC: 13AN: 1455290Hom.: 0 AF XY: 0.00000968 AC XY: 7AN XY: 723240
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GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7AN XY: 74420
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 07, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 27, 2020 | This variant is associated with the following publications: (PMID: 22763267, 23956225) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 26, 2012 | The Glu8576del variant in TTN has not been reported in the literature nor previo usly identified by our laboratory. This variant causes an in frame deletion of t he amino acid glutamic acid (Glu) at position 8576. The impact this variant has on the protein is unknown. Additional studies are needed to fully assess its c linical significance. - |
TTN-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 16, 2023 | The TTN c.29454_29456delAGA variant is predicted to result in an in-frame deletion (p.Glu9820del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.021% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179570048-CTCT-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at