rs16866490
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_133379.5(TTN):āc.13068A>Gā(p.Gln4356=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,612,694 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā ā ).
Frequency
Genomes: š 0.0058 ( 6 hom., cov: 32)
Exomes š: 0.00064 ( 12 hom. )
Consequence
TTN
NM_133379.5 synonymous
NM_133379.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.17
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 Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
?
Variant 2-178749332-T-C is Benign according to our data. Variant chr2-178749332-T-C is described in ClinVar as [Benign]. Clinvar id is 177966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178749332-T-C is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-1.17 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00578 (879/152076) while in subpopulation AFR AF= 0.0202 (839/41522). AF 95% confidence interval is 0.0191. There are 6 homozygotes in gnomad4. There are 401 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 6 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_133379.5 | c.13068A>G | p.Gln4356= | synonymous_variant | 46/46 | ENST00000360870.10 | |
TTN | NM_001267550.2 | c.11311+3792A>G | intron_variant | ENST00000589042.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000360870.10 | c.13068A>G | p.Gln4356= | synonymous_variant | 46/46 | 5 | NM_133379.5 | ||
TTN | ENST00000589042.5 | c.11311+3792A>G | intron_variant | 5 | NM_001267550.2 | P1 | |||
TTN-AS1 | ENST00000659121.1 | n.1223+6362T>C | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00576 AC: 875AN: 151958Hom.: 6 Cov.: 32
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GnomAD3 exomes AF: 0.00147 AC: 366AN: 249766Hom.: 4 AF XY: 0.00109 AC XY: 147AN XY: 135092
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GnomAD4 exome AF: 0.000640 AC: 935AN: 1460618Hom.: 12 Cov.: 36 AF XY: 0.000561 AC XY: 408AN XY: 726636
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GnomAD4 genome ? AF: 0.00578 AC: 879AN: 152076Hom.: 6 Cov.: 32 AF XY: 0.00539 AC XY: 401AN XY: 74352
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ClinVar
Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 19, 2014 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2013 | Gln4356Gln in exon 45A of TTN: This variant is not expected to have clinical sig nificance because it has been identified in 1.8% (78/4406) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS/; dbSNP rs16866490). - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 04, 2021 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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