rs72648990
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2
The NM_001267550.2(TTN):c.26528C>T(p.Thr8843Met) variant causes a missense change. The variant allele was found at a frequency of 0.000381 in 1,613,490 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T8843K) has been classified as Likely benign.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.26528C>T | p.Thr8843Met | missense_variant | 92/363 | ENST00000589042.5 | |
LOC124906100 | XR_007087318.1 | n.2562G>A | non_coding_transcript_exon_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.26528C>T | p.Thr8843Met | missense_variant | 92/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.503-20374G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000322 AC: 49AN: 152086Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000402 AC: 100AN: 248552Hom.: 0 AF XY: 0.000378 AC XY: 51AN XY: 134816
GnomAD4 exome AF: 0.000388 AC: 567AN: 1461286Hom.: 2 Cov.: 34 AF XY: 0.000393 AC XY: 286AN XY: 726900
GnomAD4 genome ? AF: 0.000315 AC: 48AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21AN XY: 74410
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 30, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | TTN: BP4 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 22, 2021 | This variant is associated with the following publications: (PMID: 24503780, 27066507) - |
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 30, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 03, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 24, 2021 | The TTN c.26528C>T; p.Thr8843Met variant (rs72648990; ClinVar Variation ID: 46782) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Given the available evidence, the clinical significance of the p.Thr8843Met variant cannot be determined with certainty. - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 06, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 28, 2017 | Variant classified as Uncertain Significance - Favor Benign. The p.Thr7599Met va riant in TTN has been identified by our laboratory in 1 Asian adult with HCM, 1 Ethiopian neonate with congenital HCM, and 2 Caucasian adults with DCM, of which 1 carried a likely pathogenic variant in another gene sufficient to explain the ir disease (Pugh 2014). Additionally, this variant has been identified in 0.1% ( 38/34342) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org/; dbSNP rs72648990) and has been reported in ClinVa r (Variation ID: 46782). Threonine (Thr) at position 7599 is not conserved in ma mmals or evolutionarily distant species, and one mammal (white rhinoceros) carri es a methionine (Met) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools do not provide stro ng support for or against an impact to the protein. In summary, while the clinic al significance of the p.Thr7599Met variant is uncertain, its frequency and lack of conservation suggest that it is more likely to be benign. - |
TTN-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2017 | - - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Genetics and Genomics Program, Sidra Medicine | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at