rs727503600

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_001267550.2(TTN):ā€‹c.55378A>Gā€‹(p.Thr18460Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000659 in 1,609,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T18460I) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.00011 ( 0 hom., cov: 32)
Exomes š‘“: 0.000061 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

3
6
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 7.62
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 made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TTN. . Gene score misZ -1.1021 (greater than the threshold 3.09). Trascript score misZ 6.9794 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, tibial muscular dystrophy, early-onset myopathy with fatal cardiomyopathy, autosomal recessive centronuclear myopathy, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 9, TTN-related myopathy, dilated cardiomyopathy 1G, arrhythmogenic right ventricular cardiomyopathy, myopathy, myofibrillar, 9, with early respiratory failure, familial isolated dilated cardiomyopathy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, autosomal recessive limb-girdle muscular dystrophy type 2J.
BP4
Computational evidence support a benign effect (MetaRNN=0.21262258).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TTNNM_001267550.2 linkuse as main transcriptc.55378A>G p.Thr18460Ala missense_variant 286/363 ENST00000589042.5 NP_001254479.2
TTN-AS1NR_038272.1 linkuse as main transcriptn.3917+1045T>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkuse as main transcriptc.55378A>G p.Thr18460Ala missense_variant 286/3635 NM_001267550.2 ENSP00000467141 P1
TTN-AS1ENST00000659121.1 linkuse as main transcriptn.502+4031T>C intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152066
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000984
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000695
AC:
17
AN:
244736
Hom.:
0
AF XY:
0.0000754
AC XY:
10
AN XY:
132652
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000266
Gnomad ASJ exome
AF:
0.000102
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000539
Gnomad OTH exome
AF:
0.000168
GnomAD4 exome
AF:
0.0000611
AC:
89
AN:
1457488
Hom.:
0
Cov.:
32
AF XY:
0.0000593
AC XY:
43
AN XY:
724742
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000340
Gnomad4 ASJ exome
AF:
0.0000385
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000531
Gnomad4 OTH exome
AF:
0.000233
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152066
Hom.:
0
Cov.:
32
AF XY:
0.0000942
AC XY:
7
AN XY:
74276
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000984
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000113
Hom.:
0
Bravo
AF:
0.000272
ExAC
AF:
0.0000579
AC:
7
EpiCase
AF:
0.00
EpiControl
AF:
0.000238

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityMar 15, 2022- -
Likely benign, criteria provided, single submitterclinical testingGeneDxApr 01, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 03, 2017- -
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingCenter for Advanced Laboratory Medicine, UC San Diego Health, University of California San DiegoMay 28, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioSep 21, 2017- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 28, 2014The Thr15892Ala variant in TTN has not been reported in individuals with cardiom yopathy or in large population studies. The affected amino acid is well conserve d in evolution, suggesting that a change would not be tolerated. Other computati onal analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT ) do not provide strong support for or against an impact to the protein. Additio nal information is needed to fully assess the clinical significance of the Thr15 892Ala variant. -
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 28, 2017- -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 27, 2019The p.T9395A variant (also known as c.28183A>G), located in coding exon 113 of the TTN gene, results from an A to G substitution at nucleotide position 28183. The threonine at codon 9395 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
21
DANN
Benign
0.87
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.86
D;D;D;.;T;D;T
M_CAP
Benign
0.044
D
MetaRNN
Benign
0.21
T;T;T;T;T;T;T
MetaSVM
Uncertain
0.14
D
MutationAssessor
Uncertain
2.8
.;.;.;M;.;.;M
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.60
T
PROVEAN
Uncertain
-3.5
D;D;.;.;D;D;.
REVEL
Uncertain
0.49
Sift
Benign
0.11
T;T;.;.;T;T;.
Polyphen
1.0
.;.;.;D;.;.;D
Vest4
0.42
MutPred
0.36
.;.;.;Loss of glycosylation at T16819 (P = 0.0414);.;.;Loss of glycosylation at T16819 (P = 0.0414);
MVP
0.41
MPC
0.46
ClinPred
0.16
T
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs727503600; hg19: chr2-179466439; COSMIC: COSV59882121; COSMIC: COSV59882121; API