rs145460295
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BP6
The NM_133379.5(TTN):c.12550G>T(p.Gly4184Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
TTN
NM_133379.5 missense
NM_133379.5 missense
Scores
8
4
3
Clinical Significance
Conservation
PhyloP100: 7.41
Genes affected
TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.818
BP6
Variant 2-178749850-C-A is Benign according to our data. Variant chr2-178749850-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166271.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_133379.5 | c.12550G>T | p.Gly4184Cys | missense_variant | 46/46 | ENST00000360870.10 | NP_596870.2 | |
TTN | NM_001267550.2 | c.11311+3274G>T | intron_variant | ENST00000589042.5 | NP_001254479.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000360870.10 | c.12550G>T | p.Gly4184Cys | missense_variant | 46/46 | 5 | NM_133379.5 | ENSP00000354117 | ||
TTN | ENST00000589042.5 | c.11311+3274G>T | intron_variant | 5 | NM_001267550.2 | ENSP00000467141 | P1 | |||
TTN-AS1 | ENST00000659121.1 | n.1224-6416C>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.000276 AC: 42AN: 151948Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000683 AC: 17AN: 248882Hom.: 0 AF XY: 0.0000445 AC XY: 6AN XY: 134836
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GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461058Hom.: 0 Cov.: 36 AF XY: 0.0000124 AC XY: 9AN XY: 726854
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GnomAD4 genome AF: 0.000276 AC: 42AN: 152066Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17AN XY: 74332
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 16, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 02, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 14, 2013 | The Gly4184Cys variant in TTN has not been previously reported in individuals wi th cardiomyopathy, but has been identified in 2/4404 African American chromosome s by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSN P rs145460295). Computational analyses (biochemical amino acid properties, conse rvation, and PolyPhen2.) do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the clinical si gnificance of the Gly4184Cys variant. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;D;D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
ClinPred
T
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at