rs149878929

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_133379.5(TTN):c.10411G>A(p.Ala3471Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000226 in 1,587,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

TTN
NM_133379.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 6.97

Publications

1 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009629548).

BP6

Variant 2-178751989-C-T is Benign according to our data. Variant chr2-178751989-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 47726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00115 (174/150690) while in subpopulation AFR AF = 0.00405 (166/41010). AF 95% confidence interval is 0.00354. There are 0 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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+1135G>A		intron	N/A	NP_001254479.2	Q8WZ42-12
TTN	NM_133379.5		c.10411G>A	p.Ala3471Thr	missense	Exon 46 of 46	NP_596870.2	Q8WZ42-6
TTN	NM_001256850.1		c.10360+1135G>A		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+1135G>A	intron	N/A	ENSP00000467141.1	Q8WZ42-12
TTN	ENST00000446966.2	TSL:1	c.11311+1135G>A	intron	N/A	ENSP00000408004.2	A0A1B0GXE3
TTN	ENST00000436599.2	TSL:1	c.11035+1135G>A	intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes

AF:

0.00115

AC:

173

AN:

150576

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00403

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000465

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000332

AC:

AN:

226146

AF XY:

0.000245

show subpopulations

Gnomad AFR exome

AF:

0.00456

Gnomad AMR exome

AF:

0.0000708

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000946

Gnomad OTH exome

AF:

0.000188

GnomAD4 exome

AF:

0.000129

AC:

185

AN:

1436832

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

714258

show subpopulations

African (AFR)

AF:

0.00498

AC:

157

AN:

31502

American (AMR)

AF:

0.000106

AC:

AN:

37638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24908

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39600

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80624

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52662

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5596

European-Non Finnish (NFE)

AF:

0.00000905

AC:

AN:

1105152

Other (OTH)

AF:

0.000186

AC:

AN:

59150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.00115

AC:

174

AN:

150690

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

AN XY:

73488

show subpopulations

African (AFR)

AF:

0.00405

AC:

166

AN:

41010

American (AMR)

AF:

0.000464

AC:

AN:

15086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5126

South Asian (SAS)

AF:

0.00

AC:

AN:

4788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67756

Other (OTH)

AF:

0.00

AC:

AN:

2090

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

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:

0.000566

Hom.:

Bravo

AF:

0.00136

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000428

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

TTN-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.53

M_CAP

Benign

0.0057

MetaRNN

Benign

0.0096

MetaSVM

Benign

-0.88

PhyloP100

7.0

PROVEAN

Benign

-0.020

REVEL

Benign

0.19

Sift

Benign

0.35

Sift4G

Benign

0.63

Polyphen

1.0

Vest4

0.55

MVP

0.55

ClinPred

0.046

GERP RS

5.9

Mutation Taster

=69/31

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

Computational scores

Splicing

Publications

Other links and lift over