rs781222763
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_001267550.2(TTN):c.96310+4A>T 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 0.0000246 in 1,460,648 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000025 ( 1 hom. )
Consequence
TTN
NM_001267550.2 splice_donor_region, intron
NM_001267550.2 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.2127
2
Clinical Significance
Conservation
PhyloP100: 1.63
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 Likely_benign. Variant got -2 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.45).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.96310+4A>T | splice_donor_region_variant, intron_variant | ENST00000589042.5 | |||
TTN-AS1 | NR_038272.1 | n.2043+1469T>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.96310+4A>T | splice_donor_region_variant, intron_variant | 5 | NM_001267550.2 | P1 | |||
TTN-AS1 | ENST00000659121.1 | n.416+20194T>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.0000445 AC: 11AN: 247228Hom.: 1 AF XY: 0.0000671 AC XY: 9AN XY: 134184
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GnomAD4 exome AF: 0.0000246 AC: 36AN: 1460648Hom.: 1 Cov.: 33 AF XY: 0.0000372 AC XY: 27AN XY: 726462
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GnomAD4 genome Cov.: 33
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33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 13, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is located in the A band of TTN (PMID: 25589632). Variants in this region may be relevant for cardiac or neuromuscular disorders (PMID: 25589632, 23975875). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 580853). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is present in population databases (rs781222763, gnomAD 0.04%). This sequence change falls in intron 346 of the TTN gene. It does not directly change the encoded amino acid sequence of the TTN protein. It affects a nucleotide within the consensus splice site. - |
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