rs397517582
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP2PP3_Strong
The NM_001267550.2(TTN):c.45895G>A(p.Glu15299Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000116 in 1,460,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 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 Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.45895G>A | p.Glu15299Lys | missense_variant, splice_region_variant | 247/363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.45895G>A | p.Glu15299Lys | missense_variant, splice_region_variant | 247/363 | 5 | NM_001267550.2 | ENSP00000467141 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.502+23034C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000808 AC: 2AN: 247536Hom.: 0 AF XY: 0.00000745 AC XY: 1AN XY: 134240
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1460202Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 726336
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 18, 2021 | Variant summary: TTN c.38191G>A (p.Glu12731Lys) results in a conservative amino acid change located in the I-band region of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 247536 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.38191G>A has been reported in the literature in an individual affected with hypertrophic cardiomyopathy (Burstein_2021). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 16, 2018 | The p.Glu12731Lys variant in TTN has not been previously reported in individual s with cardiomyopathy, but has been identified in 2/110474 of European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397517582). This variant is located in the last three bases of the exon , which is part of the 5? splice region. While computational tools do not predic t altered splicing, other computational analysis suggest that this variant may i mpact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Glu12731Lys varia nt is uncertain. ACMG/AMP Criteria applied: PM2, PP3. - |
TTN-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 28, 2024 | The TTN c.45895G>A variant is predicted to result in the amino acid substitution p.Glu15299Lys. This variant was reported along with additional TTN variants in an individual with hypertrophic cardiomyopathy (Table S2, Burstein et al. 2021. PubMed ID: 32746448). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 09, 2017 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 23, 2019 | The c.18700G>A variant (also known as p.E6234K), located in coding exon 74 of the TTN gene, results from a G to A substitution at nucleotide position 18700. This change occurs in the last base pair of coding exon 74, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, the amino acid change results in glutamic acid to lysine at codon 6234, an amino acid with similar properties. Both the nucleotide and amino acid positions are highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to weaken the efficiency of the native splice donor site, but is not predicted to have a deleterious effect on this splice donor site by BDGP; however, direct evidence is unavailable. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at