rs368770038
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6
The NM_001267550.2(TTN):c.3070G>A(p.Val1024Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1024G) has been classified 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.3070G>A | p.Val1024Ile | missense_variant | 18/363 | ENST00000589042.5 | |
TTN | NM_133379.5 | c.3070G>A | p.Val1024Ile | missense_variant | 18/46 | ENST00000360870.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.3070G>A | p.Val1024Ile | missense_variant | 18/363 | 5 | NM_001267550.2 | P1 | |
TTN | ENST00000360870.10 | c.3070G>A | p.Val1024Ile | missense_variant | 18/46 | 5 | NM_133379.5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000399 AC: 10AN: 250612Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135440
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461128Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 726892
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74358
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 22, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 11, 2014 | Variant classified as Uncertain Significance - Favor Benign. The Val1024Ile vari ant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/4406 of African American chromosomes by the NHLBI E xome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs368770038). Valine (Val) at position 1024 is conserved in mammals, though several other spec ies (softshell turtle, spiny softshell turtle, tetradon, madaka, southern platyf ish, and zebrafish) have an isoleucine (Ile) at this position, raising the possi bility that this change may be tolerated. Additional computational prediction to ols do not provide strong support for or against an impact to the protein. In su mmary, while the clinical significance of the Val1024Ile variant is uncertain, t he presence of the variant amino acid in other species suggests that it is more likely to be benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at