rs1480219250

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001267550.2(TTN):c.36865C>A(p.Arg12289Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., cov: 17)

Exomes 𝑓: 0.000025 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0940

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:

LOC124906100 (HGNC:):

LOC124906100 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.043650508).

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	UniProt
TTN	NM_001267550.2	MANE Select	c.36865C>A	p.Arg12289Ser	missense	Exon 175 of 363	NP_001254479.2	Q8WZ42-12
TTN	NM_001256850.1		c.34354+228C>A		intron	N/A	NP_001243779.1	Q8WZ42-1
TTN	NM_133378.4		c.31573+228C>A		intron	N/A	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTN	ENST00000589042.5	TSL:5 MANE Select	c.36865C>A	p.Arg12289Ser	missense	Exon 175 of 363	ENSP00000467141.1	Q8WZ42-12
TTN	ENST00000446966.2	TSL:1	c.36865C>A	p.Arg12289Ser	missense	Exon 175 of 361	ENSP00000408004.2	A0A1B0GXE3
TTN	ENST00000436599.2	TSL:1	c.36589C>A	p.Arg12197Ser	missense	Exon 173 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes

AF:

0.0000537

AC:

AN:

130472

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00188

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000163

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000336

AC:

AN:

59490

AF XY:

0.0000336

show subpopulations

Gnomad AFR exome

AF:

0.000183

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000604

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1137974

Hom.:

Cov.:

AF XY:

0.0000210

AC XY:

AN XY:

571138

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26382

American (AMR)

AF:

0.00

AC:

AN:

35904

Ashkenazi Jewish (ASJ)

AF:

0.00100

AC:

AN:

20982

East Asian (EAS)

AF:

0.00

AC:

AN:

36518

South Asian (SAS)

AF:

0.00

AC:

AN:

71990

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35968

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3386

European-Non Finnish (NFE)

AF:

0.00000583

AC:

AN:

857684

Other (OTH)

AF:

0.0000203

AC:

AN:

49160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000537

AC:

AN:

130472

Hom.:

Cov.:

AF XY:

0.0000963

AC XY:

AN XY:

62310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

34032

American (AMR)

AF:

0.00

AC:

AN:

12636

Ashkenazi Jewish (ASJ)

AF:

0.00188

AC:

AN:

3194

East Asian (EAS)

AF:

0.00

AC:

AN:

4404

South Asian (SAS)

AF:

0.00

AC:

AN:

3598

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

302

European-Non Finnish (NFE)

AF:

0.0000163

AC:

AN:

61444

Other (OTH)

AF:

0.00

AC:

AN:

1672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.72

CADD

Benign

5.3

(source)

DANN

Benign

0.76

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.65

M_CAP

Benign

0.031

MetaRNN

Benign

0.044

MetaSVM

Benign

-1.0

PhyloP100

0.094

Vest4

0.081

MVP

0.29

MPC

0.094

ClinPred

0.020

GERP RS

1.4

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