rs397517495
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate
The NM_001267550.2(TTN):c.20742T>A(p.Phe6914Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,612,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.20742T>A | p.Phe6914Leu | missense_variant | 71/363 | ENST00000589042.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.20742T>A | p.Phe6914Leu | missense_variant | 71/363 | 5 | NM_001267550.2 | P1 | |
ENST00000590024.1 | n.2006A>T | non_coding_transcript_exon_variant | 1/1 | ||||||
TTN-AS1 | ENST00000659121.1 | n.503-9042A>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152176Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248152Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134648
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1460772Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 726620
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152176Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74334
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 05, 2013 | The Phe5670Leu variant in TTN has been identified by our laboratory in 1 Caucasi an individual with DCM (LMM unpublished data) and was not identified in large po pulation studies. Phenylalanine (Phe) at position 5670 is not well conserved in evolution and 2 species (chicken and lizard) carry a leucine (Leu; this variant) at this position, suggesting that this change may be tolerated. Other computati onal analyses (biochemical amino acid properties, AlignGVGD, PolyPhen, and SIFT) do not provide strong support for or against an impact to the protein. At this time, additional information is needed to fully assess the clinical significance of the Phe5670Leu variant. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 06, 2017 | A variant of uncertain significance has been identified in the TTN gene. The F6597L variant has been reported in one patient with DCM, however, this patient also harbored a nonsense variant in the TTN gene (Pugh et al., 2014). The F5670L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the F5670L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species and where leucine (L) is present as the wild type in at least two species. Finally, this is a missense variant in a gene in which most reported pathogenic variants associated with cardiomyopathy are truncating/loss-of-function (Stenson et al., 2014). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at