NM_133379.5:c.15285_15317dupCTCCACACCCCCAGGAGAGACTCTAGAGCGATA

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM4BP6_Very_StrongBS1

The NM_133379.5(TTN):c.15285_15317dupCTCCACACCCCCAGGAGAGACTCTAGAGCGATA(p.Tyr5106_Ser5107insSerThrProProGlyGluThrLeuGluArgTyr) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 148,292 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y5106Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 8 hom. )

Failed GnomAD Quality Control

Consequence

TTN
NM_133379.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:11

Conservation

PhyloP100: 0.853

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 links:

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]

TTN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_133379.5.

BP6

Variant 2-178747082-A-ATATCGCTCTAGAGTCTCTCCTGGGGGTGTGGAG is Benign according to our data. Variant chr2-178747082-A-ATATCGCTCTAGAGTCTCTCCTGGGGGTGTGGAG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00259 (384/148292) while in subpopulation NFE AF = 0.00462 (308/66642). AF 95% confidence interval is 0.0042. There are 0 homozygotes in GnomAd4. There are 169 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_133379.5 link	c.15285_15317dupCTCCACACCCCCAGGAGAGACTCTAGAGCGATA	p.Tyr5106_Ser5107insSerThrProProGlyGluThrLeuGluArgTyr	disruptive_inframe_insertion	Exon 46 of 46	ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7
TTN	NM_001267550.2 link	c.11312-5194_11312-5162dupCTCCACACCCCCAGGAGAGACTCTAGAGCGATA		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
TTN	ENST00000360870.10 link	c.15285_15317dupCTCCACACCCCCAGGAGAGACTCTAGAGCGATA	p.Tyr5106_Ser5107insSerThrProProGlyGluThrLeuGluArgTyr	disruptive_inframe_insertion	Exon 46 of 46	5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6
TTN	ENST00000589042.5 link	c.11312-5194_11312-5162dupCTCCACACCCCCAGGAGAGACTCTAGAGCGATA		intron_variant	Intron 47 of 362	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.00259

AC:

384

AN:

148172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000501

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00201

Gnomad ASJ

AF:

0.00117

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00174

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00462

Gnomad OTH

AF:

0.00196

GnomAD2 exomes

AF:

0.00270

AC:

673

AN:

249514

AF XY:

0.00261

show subpopulations

Gnomad AFR exome

AF:

0.000749

Gnomad AMR exome

AF:

0.000960

Gnomad ASJ exome

AF:

0.000505

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00186

Gnomad NFE exome

AF:

0.00502

Gnomad OTH exome

AF:

0.00248

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00312

AC:

4551

AN:

1458100

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

2222

AN XY:

725458

show subpopulations

African (AFR)

AF:

0.000539

AC:

AN:

33390

American (AMR)

AF:

0.00110

AC:

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.000500

AC:

AN:

26022

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

53322

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00381

AC:

4220

AN:

1108944

Other (OTH)

AF:

0.00246

AC:

148

AN:

60252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.407

Heterozygous variant carriers

215

430

646

861

1076

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<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

AF:

0.00259

AC:

384

AN:

148292

Hom.:

Cov.:

AF XY:

0.00233

AC XY:

169

AN XY:

72482

show subpopulations

African (AFR)

AF:

0.000499

AC:

AN:

40050

American (AMR)

AF:

0.00201

AC:

AN:

14940

Ashkenazi Jewish (ASJ)

AF:

0.00117

AC:

AN:

3428

East Asian (EAS)

AF:

0.00

AC:

AN:

4994

South Asian (SAS)

AF:

0.00

AC:

AN:

4668

European-Finnish (FIN)

AF:

0.00174

AC:

AN:

10334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.00462

AC:

308

AN:

66642

Other (OTH)

AF:

0.00193

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00296

Hom.:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Oct 23, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 27, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:provider interpretation

p.Thr5102_Glu5112dup (T5102_E5112dup, c.15285_15317dup33:) in exon 46 of the TTN gene (NM_133379.3, alternate transcript). Seen in a patient in our center with LVNC and reduced systolic function. Given the location, lack of case data, and frequency in ExAC, we consider this variant a variant of uncertain significance, probably benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been reported in association with disease. Based on the genomic position (hg19 ) and https://cardiodb.org/titin/ it appears the variant is in the I-band distant from the A band. To date it appears that pathogenic variants in TTN are in the A band (or the I band near the A band). ExAC: 0.6% (376/66452) European chromosomes. -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTN: PM4, BS2 -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:4

Apr 09, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Thr5102_Glu5112dup in exon 45A of TTN: This variant is not expected to be clin ically significant because it has been identified in 0.6% (376/66452) European c hromosomes, including 2 homozygotes, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397517815) and in 1.1% (4/372) Caucasian control chromosomes tested by our laboratory (LMM unpublished data). -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 17, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:2

Mar 28, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 15, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TTN-related disorder

Benign:1

Aug 30, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.85

Mutation Taster

=85/15

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over