rs377276702
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_003283.6(TNNT1):āc.788A>Gā(p.Lys263Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,613,692 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 30)
Exomes š: 0.000016 ( 0 hom. )
Consequence
TNNT1
NM_003283.6 missense
NM_003283.6 missense
Scores
2
6
5
Clinical Significance
Conservation
PhyloP100: 6.96
Genes affected
TNNT1 (HGNC:11948): (troponin T1, slow skeletal type) This gene encodes a protein that is a subunit of troponin, which is a regulatory complex located on the thin filament of the sarcomere. This complex regulates striated muscle contraction in response to fluctuations in intracellular calcium concentration. This complex is composed of three subunits: troponin C, which binds calcium, troponin T, which binds tropomyosin, and troponin I, which is an inhibitory subunit. This protein is the slow skeletal troponin T subunit. Mutations in this gene cause nemaline myopathy type 5, also known as Amish nemaline myopathy, a neuromuscular disorder characterized by muscle weakness and rod-shaped, or nemaline, inclusions in skeletal muscle fibers which affects infants, resulting in death due to respiratory insufficiency, usually in the second year. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNT1 | NM_003283.6 | c.788A>G | p.Lys263Arg | missense_variant | 13/14 | ENST00000588981.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNT1 | ENST00000588981.6 | c.788A>G | p.Lys263Arg | missense_variant | 13/14 | 1 | NM_003283.6 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152042Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250918Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135798
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461650Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 727100
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152042Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 74260
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Nemaline myopathy 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2022 | Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 534400). This variant has not been reported in the literature in individuals affected with TNNT1-related conditions. This variant is present in population databases (rs377276702, gnomAD 0.007%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 263 of the TNNT1 protein (p.Lys263Arg). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
Sift4G
Benign
T;T;T;D;D;T;T;T
Polyphen
D;D;D;.;D;.;.;.
Vest4
MVP
MPC
1.4
ClinPred
D
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at