rs374616494

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_133379.5(TTN):c.11253A>G(p.Arg3751Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000986 in 1,612,644 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

TTN
NM_133379.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.438

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 2-178751147-T-C is Benign according to our data. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178751147-T-C is described in CliVar as Likely_benign. Clinvar id is 47737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.438 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_133379.5 link	c.11253A>G	p.Arg3751Arg	synonymous_variant	Exon 46 of 46	ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7
TTN	NM_001267550.2 link	c.11311+1977A>G		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.11253A>G	p.Arg3751Arg	synonymous_variant	Exon 46 of 46	5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6
TTN	ENST00000589042.5 link	c.11311+1977A>G		intron_variant	Intron 47 of 362	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000213

AC:

AN:

249044

AF XY:

0.000193

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000378

Gnomad ASJ exome

AF:

0.00340

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000446

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000102

AC:

149

AN:

1460632

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

726556

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.000314

AC:

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.00322

AC:

AN:

26058

East Asian (EAS)

AF:

0.00

AC:

AN:

39614

South Asian (SAS)

AF:

0.00

AC:

AN:

86160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0000315

AC:

AN:

1111402

Other (OTH)

AF:

0.000265

AC:

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000658

AC:

AN:

152012

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41434

American (AMR)

AF:

0.000131

AC:

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67934

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.000447

Hom.:

Bravo

AF:

0.000159

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 22, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arg3751Arg 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. This variant has been identified in 0.01% (1/ 7006) of European American chromosomes from a broad population by the NHLBI Exom e Sequencing Project (http://evs.gs.washington.edu/EVS/) Arg3751Arg in exon 45A of TTN (allele frequency = 0.01%, 1/7006) ** -

TTN-related disorder

Benign:1

Apr 28, 2020

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). -

not provided

Benign:1

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTN: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

2.1

(source)

DANN

Benign

0.63

PhyloP100

-0.44

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over