rs144905085

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_133379.5(TTN):c.14489A>G(p.Gln4830Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000164 in 1,613,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00083 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

TTN
NM_133379.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 4.20

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005445838).

BP6

Variant 2-178747911-T-C is Benign according to our data. Variant chr2-178747911-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 166259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_133379.5 linkuse as main transcript	c.14489A>G	p.Gln4830Arg	missense_variant	46/46	ENST00000360870.10
TTN	NM_001267550.2 linkuse as main transcript	c.11311+5213A>G		intron_variant		ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000360870.10 linkuse as main transcript	c.14489A>G	p.Gln4830Arg	missense_variant	46/46	5	NM_133379.5		Q8WZ42-6
TTN	ENST00000589042.5 linkuse as main transcript	c.11311+5213A>G		intron_variant		5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.1223+4941T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000842

AC:

128

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00302

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000204

AC:

AN:

250170

Hom.:

AF XY:

0.000200

AC XY:

AN XY:

135258

show subpopulations

Gnomad AFR exome

AF:

0.00285

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000938

AC:

137

AN:

1461058

Hom.:

Cov.:

AF XY:

0.0000839

AC XY:

AN XY:

726850

show subpopulations

Gnomad4 AFR exome

AF:

0.00317

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000835

AC:

127

AN:

152126

Hom.:

Cov.:

AF XY:

0.000955

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00298

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000106

Hom.:

Bravo

AF:

0.000986

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	TTN: BP4, BS1 -
not provided, no classification provided	clinical testing	GeneDx	Oct 29, 2014	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Gln4830Arg in Exon 45A of TTN: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (12/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs144905085). -

TTN-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.30

M_CAP

Benign

0.021

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.90

MutationTaster

Benign

1.0

D;D;D;D;D;D;N

PROVEAN

Benign

-0.62

REVEL

Benign

0.13

Sift

Pathogenic

0.0

Sift4G

Benign

0.35

Polyphen

0.0030

Vest4

0.34

MVP

0.30

ClinPred

0.068

GERP RS

4.5

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over