2-178553355-C-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001267550.2(TTN):​c.89545G>T​(p.Val29849Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,448,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0710

Publications

0 publications found
Variant links:
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]
TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.15117449).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.89545G>T p.Val29849Phe missense_variant Exon 335 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.89545G>T p.Val29849Phe missense_variant Exon 335 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000414
AC:
6
AN:
1448010
Hom.:
0
Cov.:
33
AF XY:
0.00000417
AC XY:
3
AN XY:
719422
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33388
American (AMR)
AF:
0.00
AC:
0
AN:
44622
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25976
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39552
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85912
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
45628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5742
European-Non Finnish (NFE)
AF:
0.00000542
AC:
6
AN:
1107122
Other (OTH)
AF:
0.00
AC:
0
AN:
60068
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 05, 2013
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The Val27281Phe variant in TTN has not been reported in the literature nor previ ously identified by our laboratory. This variant has also not been identified in large European American and African American populations by the NHLBI Exome Seq uencing Project (http://evs.gs.washington.edu/EVS), though it may be present in other populations. Computational analyses (biochemical amino acid properties, co nservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. At this time, additional information is neede d to fully assess the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.069
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
0.46
DANN
Benign
0.73
Eigen
Benign
-0.88
Eigen_PC
Benign
-0.96
FATHMM_MKL
Benign
0.068
N
LIST_S2
Uncertain
0.89
D;D;D;.;D;D;D
M_CAP
Benign
0.063
D
MetaRNN
Benign
0.15
T;T;T;T;T;T;T
MetaSVM
Benign
-0.68
T
MutationAssessor
Uncertain
2.2
.;.;.;M;.;.;M
PhyloP100
-0.071
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-2.2
N;N;.;.;N;N;.
REVEL
Uncertain
0.32
Sift
Uncertain
0.028
D;D;.;.;D;D;.
Polyphen
0.062
.;.;.;B;.;.;B
Vest4
0.37
MutPred
0.65
.;.;.;Loss of ubiquitination at K28211 (P = 0.0755);.;.;Loss of ubiquitination at K28211 (P = 0.0755);
MVP
0.32
MPC
0.12
ClinPred
0.10
T
GERP RS
-5.7
Mutation Taster
=85/15
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs727504493; hg19: chr2-179418082; API