rs774506028
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_001267550.2(TTN):c.4480G>T(p.Gly1494Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_001267550.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.4480G>T | p.Gly1494Cys | missense_variant, splice_region_variant | 25/363 | ENST00000589042.5 | NP_001254479.2 | |
TTN | NM_133379.5 | c.4480G>T | p.Gly1494Cys | missense_variant, splice_region_variant | 25/46 | ENST00000360870.10 | NP_596870.2 | |
LOC101927055 | NR_120594.1 | n.779C>A | non_coding_transcript_exon_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.4480G>T | p.Gly1494Cys | missense_variant, splice_region_variant | 25/363 | 5 | NM_001267550.2 | ENSP00000467141 | P1 | |
TTN | ENST00000360870.10 | c.4480G>T | p.Gly1494Cys | missense_variant, splice_region_variant | 25/46 | 5 | NM_133379.5 | ENSP00000354117 | ||
TTN-AS1 | ENST00000659121.1 | n.5131C>A | non_coding_transcript_exon_variant | 12/13 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250834Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135576
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461688Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727160
GnomAD4 genome Cov.: 33
ClinVar
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 | Aug 10, 2022 | This variant is located in the Z band of TTN (PMID: 25589632). Variants in this region may be clinically relevant, but have not been definitively shown to cause cardiomyopathy or neuromuscular disease (PMID: 27493940, 32778822). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1494 of the TTN protein (p.Gly1494Cys). This variant also falls at the last nucleotide of exon 25, which is part of the consensus splice site for this exon. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at