rs200066725

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_133379.5(TTN):c.13589T>G(p.Ile4530Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,611,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

TTN
NM_133379.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.805

Publications

2 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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12065235).

BP6

Variant 2-178748811-A-C is Benign according to our data. Variant chr2-178748811-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178874.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133379.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTN	NM_001267550.2	MANE Select	c.11311+4313T>G		intron	N/A	NP_001254479.2	Q8WZ42-12
TTN	NM_133379.5		c.13589T>G	p.Ile4530Arg	missense	Exon 46 of 46	NP_596870.2	Q8WZ42-6
TTN	NM_001256850.1		c.10360+4313T>G		intron	N/A	NP_001243779.1	Q8WZ42-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TTN	ENST00000589042.5	TSL:5 MANE Select	c.11311+4313T>G	intron	N/A	ENSP00000467141.1	Q8WZ42-12
TTN	ENST00000446966.2	TSL:1	c.11311+4313T>G	intron	N/A	ENSP00000408004.2	A0A1B0GXE3
TTN	ENST00000436599.2	TSL:1	c.11035+4313T>G	intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

151920

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000105

AC:

AN:

248786

AF XY:

0.000112

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000877

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000178

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000118

AC:

172

AN:

1459676

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

726048

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33334

American (AMR)

AF:

0.000112

AC:

AN:

44474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85748

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53230

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.000133

AC:

148

AN:

1111220

Other (OTH)

AF:

0.000149

AC:

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000987

AC:

AN:

151920

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41402

American (AMR)

AF:

0.0000657

AC:

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

67908

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.000182

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.0000989

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.42

CADD

Benign

7.5

(source)

DANN

Benign

0.90

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.55

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.29

M_CAP

Benign

0.031

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

PhyloP100

0.81

PROVEAN

Benign

-1.5

REVEL

Benign

0.058

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.022

Polyphen

0.14

Vest4

0.40

MVP

0.51

ClinPred

0.034

GERP RS

3.7

Mutation Taster

=79/21

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over