rs397517820
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_133379.5(TTN):c.16264C>G(p.Pro5422Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,270 control chromosomes in the GnomAD database, with no homozygous occurrence. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
TTN
NM_133379.5 missense
NM_133379.5 missense
Scores
5
10
Clinical Significance
Conservation
PhyloP100: 3.38
Publications
0 publications found
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]
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TTN | NM_133379.5 | c.16264C>G | p.Pro5422Ala | missense_variant | Exon 46 of 46 | ENST00000360870.10 | NP_596870.2 | |
| TTN | NM_001267550.2 | c.11312-4215C>G | intron_variant | Intron 47 of 362 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000360870.10 | c.16264C>G | p.Pro5422Ala | missense_variant | Exon 46 of 46 | 5 | NM_133379.5 | ENSP00000354117.4 | ||
| TTN | ENST00000589042.5 | c.11312-4215C>G | intron_variant | Intron 47 of 362 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461270Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 726948 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461270
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
726948
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33438
American (AMR)
AF:
AC:
0
AN:
44686
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26108
East Asian (EAS)
AF:
AC:
0
AN:
39660
South Asian (SAS)
AF:
AC:
0
AN:
86240
European-Finnish (FIN)
AF:
AC:
0
AN:
53394
Middle Eastern (MID)
AF:
AC:
0
AN:
5760
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111624
Other (OTH)
AF:
AC:
0
AN:
60360
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Nov 23, 2011
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The Pro5422Ala variant (TTN) has not been previously reported but has been ident ified by our laboratory in 1 individual with DCM (this individual carried 3 addi tional variants of unknown significance). Evolutionary conservation data and com putational predictions are not available for this variant and the clinical signi ficance cannot be determined at this time. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Uncertain
D
MetaSVM
Benign
T
PhyloP100
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Loss of catalytic residue at P5422 (P = 0.1001);
MVP
ClinPred
T
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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