rs200284932

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_133379.5(TTN):​c.10617T>C​(p.His3539His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000438 in 1,613,206 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00041 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00044 ( 2 hom. )

Consequence

TTN
NM_133379.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.20
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 Benign. Variant got -15 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.38).
BP6
Variant 2-178751783-A-G is Benign according to our data. Variant chr2-178751783-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 47728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751783-A-G is described in Lovd as [Likely_benign]. Variant chr2-178751783-A-G is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=2.2 with no splicing effect.
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_133379.5 linkc.10617T>C p.His3539His synonymous_variant Exon 46 of 46 ENST00000360870.10 NP_596870.2 Q8WZ42-6Q7Z3B7
TTNNM_001267550.2 linkc.11311+1341T>C intron_variant Intron 47 of 362 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000360870.10 linkc.10617T>C p.His3539His synonymous_variant Exon 46 of 46 5 NM_133379.5 ENSP00000354117.4 Q8WZ42-6
TTNENST00000589042.5 linkc.11311+1341T>C intron_variant Intron 47 of 362 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.000414
AC:
63
AN:
152000
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.0153
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000736
Gnomad OTH
AF:
0.000959
GnomAD3 exomes
AF:
0.000795
AC:
199
AN:
250208
Hom.:
2
AF XY:
0.000754
AC XY:
102
AN XY:
135226
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.0169
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000177
Gnomad OTH exome
AF:
0.00164
GnomAD4 exome
AF:
0.000441
AC:
644
AN:
1461088
Hom.:
2
Cov.:
39
AF XY:
0.000473
AC XY:
344
AN XY:
726830
show subpopulations
Gnomad4 AFR exome
AF:
0.000508
Gnomad4 AMR exome
AF:
0.0000672
Gnomad4 ASJ exome
AF:
0.0169
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000954
Gnomad4 OTH exome
AF:
0.00121
GnomAD4 genome
AF:
0.000414
AC:
63
AN:
152118
Hom.:
1
Cov.:
32
AF XY:
0.000403
AC XY:
30
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.0153
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000736
Gnomad4 OTH
AF:
0.000949
Alfa
AF:
0.000989
Hom.:
0
Bravo
AF:
0.000570
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.000437
EpiControl
AF:
0.000415

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 27, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 24, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

His3539His in exon 45A of TTN: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 0.1% (6/7020) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS). His3539His in exon 45A of TTN (al lele frequency = 0.1%, 6/7020) ** -

Mar 23, 2017
Eurofins Ntd Llc (ga)
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:2
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

TTN: BP4, BP7 -

TTN-related disorder Benign:1
Feb 20, 2024
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy Benign:1
Aug 18, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.38
CADD
Benign
16
DANN
Benign
0.70

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: rs200284932; hg19: chr2-179616510; API