chr3-52451412-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PP3_ModerateBS1_SupportingBS2
The NM_003280.3(TNNC1):c.433G>A(p.Asp145Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D145E) has been classified as Uncertain significance.
Frequency
Consequence
NM_003280.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNC1 | NM_003280.3 | c.433G>A | p.Asp145Asn | missense_variant | 5/6 | ENST00000232975.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNC1 | ENST00000232975.8 | c.433G>A | p.Asp145Asn | missense_variant | 5/6 | 1 | NM_003280.3 | P1 | |
TNNC1 | ENST00000496590.1 | downstream_gene_variant | 2 | ||||||
TNNC1 | ENST00000461086.1 | downstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250856Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135796
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461858Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727228
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 23, 2022 | Identified in a patient with sudden unexplained death (SUD) while driving who also harbored a variant in the MYBPC3 gene (Christiansen et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30681346, 27650965) - |
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 10, 2022 | - - |
Dilated cardiomyopathy 1Z;C2750472:Hypertrophic cardiomyopathy 13 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 145 of the TNNC1 protein (p.Asp145Asn). This variant is present in population databases (rs142759728, gnomAD 0.003%). This missense change has been observed in individual(s) with sudden unexplained death (PMID: 27650965). ClinVar contains an entry for this variant (Variation ID: 409874). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Dilated cardiomyopathy 1Z Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at