rs756475184
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_001267550.2(TTN):c.33172+4G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000337 in 1,603,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
TTN
NM_001267550.2 splice_donor_region, intron
NM_001267550.2 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0001318
2
Clinical Significance
Conservation
PhyloP100: 0.312
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]
TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
BP6
?
Variant 2-178681657-C-T is Benign according to our data. Variant chr2-178681657-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229419.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}. Variant chr2-178681657-C-T is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.33172+4G>A | splice_donor_region_variant, intron_variant | ENST00000589042.5 | |||
LOC124906100 | XR_007087318.1 | n.2186-32097C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.33172+4G>A | splice_donor_region_variant, intron_variant | 5 | NM_001267550.2 | P1 | |||
TTN-AS1 | ENST00000659121.1 | n.503-52847C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000224 AC: 34AN: 151904Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000499 AC: 12AN: 240252Hom.: 0 AF XY: 0.0000384 AC XY: 5AN XY: 130242
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GnomAD4 exome AF: 0.0000138 AC: 20AN: 1451614Hom.: 0 Cov.: 31 AF XY: 0.0000125 AC XY: 9AN XY: 721762
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GnomAD4 genome ? AF: 0.000224 AC: 34AN: 151904Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17AN XY: 74208
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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) | Jun 20, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 09, 2020 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 23, 2015 | The c.29440+4G>A variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.1% (9/9784) African chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Th is variant is located in the 5' splice region. Computational tools do not sugges t an impact to splicing. However, this information is not predictive enough to r ule out pathogenicity. In summary, the clinical significance of the c.29440+4G>A variant is uncertain. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at