rs72647902

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001267550.2(TTN):c.11311+3847G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000536 in 1,611,436 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).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 0 hom. )

Consequence

TTN
NM_001267550.2 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 0.226

Publications

9 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017016172).

BP6

Variant 2-178749277-C-A is Benign according to our data. Variant chr2-178749277-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47748.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	NM_001267550.2	MANE Select	c.11311+3847G>T		intron	N/A	NP_001254479.2
TTN	NM_133379.5		c.13123G>T	p.Ala4375Ser	missense	Exon 46 of 46	NP_596870.2
TTN	NM_001256850.1		c.10360+3847G>T		intron	N/A	NP_001243779.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TTN	ENST00000589042.5	TSL:5 MANE Select	c.11311+3847G>T	intron	N/A	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.11311+3847G>T	intron	N/A	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.11035+3847G>T	intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000314

AC:

AN:

248520

AF XY:

0.000312

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000437

Gnomad NFE exome

AF:

0.000498

Gnomad OTH exome

AF:

0.000662

GnomAD4 exome

AF:

0.000562

AC:

820

AN:

1459344

Hom.:

Cov.:

AF XY:

0.000522

AC XY:

379

AN XY:

726070

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33424

American (AMR)

AF:

0.000291

AC:

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.000270

AC:

AN:

51804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000689

AC:

766

AN:

1111420

Other (OTH)

AF:

0.000381

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

104

155

207

259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<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:

0.000283

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41526

American (AMR)

AF:

0.000328

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

67936

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.000648

Hom.:

Bravo

AF:

0.000389

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000296

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.000546

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Nov 14, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 29, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a large cohort of individuals with dilated cardiomyopathy; however, no details are provided (Haas et al., 2015); Observed in 0.0454% (57/125522) of alleles from individuals of European (non-Finnish) background in large population cohorts (Lek et al., 2016); Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; In silico analysis, which includes splice predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25163546)

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTN: PM2, BP4

not specified

Benign:2

Aug 16, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ala4375Ser in exon 45A of TTN: This variant is not expected to have clinical s ignificance because it has been identified in 0.05% (57/125522) of European chro mosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute .org; dbSNP rs72647902). In addition, this variant is located in an exon that is only present in an alternate transcript (Novex-3), whose function is unclear. A CMG/AMP Criteria applied: BS1; BP4.

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP1

TTN-related disorder

Uncertain:1

Apr 28, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TTN c.13123G>T variant is predicted to result in the amino acid substitution p.Ala4375Ser. This variant is referred to as c.11311+3847G>T (intronic) with an alternate transcript NM_001267550. This variant was reported in a cohort of individuals with dilated cardiomyopathy; however, detailed clinical information was not available (Table S6, Haas et al. 2015. PubMed ID: 25163546). This variant is reported in 0.046% of alleles in individuals of European (Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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

Uncertain:1

Feb 03, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.43

M_CAP

Benign

0.020

MetaRNN

Benign

0.017

MetaSVM

Benign

-1.0

PhyloP100

0.23

PROVEAN

Benign

0.34

REVEL

Benign

0.028

Sift

Pathogenic

0.0

Sift4G

Benign

0.74

Polyphen

0.082

Vest4

0.24

MVP

0.44

ClinPred

0.080

GERP RS

4.2

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over