rs1553479603
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PM2PP3PP5_Moderate
The NM_001267550.2(TTN):c.107198_107223+4del variant causes a splice donor, splice donor region, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,601,458 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. I35733I) has been classified as Likely benign.
Frequency
Consequence
NM_001267550.2 splice_donor, splice_donor_region, coding_sequence, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.107198_107223+4del | splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant | 360/363 | ENST00000589042.5 | ||
TTN-AS1 | NR_038272.1 | n.219+4890_219+4919del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.107198_107223+4del | splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant | 360/363 | 5 | NM_001267550.2 | P1 | ||
TTN-AS1 | ENST00000659121.1 | n.416+4890_416+4919del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1449270Hom.: 0 AF XY: 0.00000139 AC XY: 1AN XY: 719512
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74348
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 | Jan 31, 2024 | The c.99494_99519+4del variant in TTN has been identified in a child with DCM (LMM data). It has also been identified in 0.0003% (3/1172860) of European chromosomes in gnomAD (http://gnomad.broadinstitute.org, v4.0.0). This variant is a 30 base-pair deletion that spans the canonical +1 and +2 positions in the 5' splice site consensus sequence of intron 309 and is therefore expected to disrupt splicing and lead to a truncated or absent protein. TTN truncating variants encoded in constitutive exons (PSI >95%) have been found to be significantly associated with DCM regardless of their position in titin (Roberts 2015 PMID:25589632, Schafer 2017 PMID:27869827). The c.99494_99519+4del variant is located in such a highly expressed exon in the M band. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at