rs397517750
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001267550.2(TTN):c.90778_90779insT(p.Tyr30260LeufsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,516 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y30260Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001267550.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.90778_90779insT | p.Tyr30260LeufsTer12 | frameshift_variant | 335/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.2043+9762dup | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.90778_90779insT | p.Tyr30260LeufsTer12 | frameshift_variant | 335/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.416+28487dup | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461516Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727030
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Primary dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 08, 2015 | The p.Tyr27692fs variant in TTN has been previously identified by our laboratory in 1 individual with DCM and was absent from large population studies. This va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 27692 and leads to a premature termination codon 12 amino acids downstream. This alteration is then predicted to lead to a trunca ted or absent protein. Frameshift and other truncating variants in TTN are stron gly associated with DCM, particularly if they are located in the exons encoding for the A-band region of the protein (Herman 2012, Pugh 2014), where this varian t is located. In summary, although additional studies are required to fully esta blish its clinical significance, the p.Tyr27692fs variant is likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at