rs151253841
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_133379.5(TTN):โc.16001C>Tโ(p.Pro5334Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,609,320 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (โ โ ).
Frequency
Genomes: ๐ 0.0010 ( 5 hom., cov: 32)
Exomes ๐: 0.0017 ( 57 hom. )
Consequence
TTN
NM_133379.5 missense
NM_133379.5 missense
Scores
4
3
7
Clinical Significance
Conservation
PhyloP100: 10.0
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 -20 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0089713335).
BP6
Variant 2-178746399-G-A is Benign according to our data. Variant chr2-178746399-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 47792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178746399-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00105 (159/152014) while in subpopulation SAS AF= 0.0284 (137/4820). AF 95% confidence interval is 0.0245. There are 5 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_133379.5 | c.16001C>T | p.Pro5334Leu | missense_variant | 46/46 | ENST00000360870.10 | NP_596870.2 | |
TTN | NM_001267550.2 | c.11312-4478C>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.16001C>T | p.Pro5334Leu | missense_variant | 46/46 | 5 | NM_133379.5 | ENSP00000354117.4 | ||
TTN | ENST00000589042.5 | c.11312-4478C>T | intron_variant | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes AF: 0.000994 AC: 151AN: 151896Hom.: 5 Cov.: 32
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GnomAD3 exomes AF: 0.00341 AC: 842AN: 246704Hom.: 15 AF XY: 0.00462 AC XY: 616AN XY: 133372
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GnomAD4 exome AF: 0.00171 AC: 2491AN: 1457306Hom.: 57 Cov.: 33 AF XY: 0.00245 AC XY: 1778AN XY: 724612
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GnomAD4 genome AF: 0.00105 AC: 159AN: 152014Hom.: 5 Cov.: 32 AF XY: 0.00143 AC XY: 106AN XY: 74334
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 20, 2014 | p.Pro5334Leu in exon 45A of TTN: This variant is not expected to have clinical s ignificance because it has been identified in 3.0% (482/16240) of South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs151253841). - |
Benign, criteria provided, single submitter | clinical testing | Al Jalila Childrenโs Genomics Center, Al Jalila Childrens Speciality Hospital | Mar 19, 2020 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 03, 2019 | - - |
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Limb-girdle muscular dystrophy, recessive Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Early-onset myopathy with fatal cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Dilated Cardiomyopathy, Dominant Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Tibial muscular dystrophy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D;D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
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