rs66677602

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_133379.5(TTN):c.15416G>T(p.Arg5139Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0531 in 1,613,354 control chromosomes in the GnomAD database, including 3,938 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.050 ( 385 hom., cov: 32)

Exomes 𝑓: 0.053 ( 3553 hom. )

Consequence

TTN
NM_133379.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.758

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011175871).

BP6

Variant 2-178746984-C-A is Benign according to our data. Variant chr2-178746984-C-A is described in ClinVar as [Benign]. Clinvar id is 47786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178746984-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_133379.5 linkuse as main transcript	c.15416G>T	p.Arg5139Met	missense_variant	46/46	ENST00000360870.10	NP_596870.2
TTN	NM_001267550.2 linkuse as main transcript	c.11312-5063G>T		intron_variant		ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10 linkuse as main transcript	c.15416G>T	p.Arg5139Met	missense_variant	46/46	5	NM_133379.5	ENSP00000354117		Q8WZ42-6
TTN	ENST00000589042.5 linkuse as main transcript	c.11312-5063G>T		intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.1223+4014C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0503

AC:

7632

AN:

151880

Hom.:

384

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0116

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.137

Gnomad ASJ

AF:

0.0488

Gnomad EAS

AF:

0.196

Gnomad SAS

AF:

0.0234

Gnomad FIN

AF:

0.0512

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0454

Gnomad OTH

AF:

0.0466

GnomAD3 exomes

AF:

0.0803

AC:

20132

AN:

250760

Hom.:

1756

AF XY:

0.0709

AC XY:

9611

AN XY:

135516

show subpopulations

Gnomad AFR exome

AF:

0.0109

Gnomad AMR exome

AF:

0.241

Gnomad ASJ exome

AF:

0.0485

Gnomad EAS exome

AF:

0.217

Gnomad SAS exome

AF:

0.0192

Gnomad FIN exome

AF:

0.0526

Gnomad NFE exome

AF:

0.0445

Gnomad OTH exome

AF:

0.0666

GnomAD4 exome

AF:

0.0534

AC:

78002

AN:

1461356

Hom.:

3553

Cov.:

AF XY:

0.0516

AC XY:

37485

AN XY:

726982

show subpopulations

Gnomad4 AFR exome

AF:

0.00924

Gnomad4 AMR exome

AF:

0.229

Gnomad4 ASJ exome

AF:

0.0473

Gnomad4 EAS exome

AF:

0.202

Gnomad4 SAS exome

AF:

0.0202

Gnomad4 FIN exome

AF:

0.0546

Gnomad4 NFE exome

AF:

0.0453

Gnomad4 OTH exome

AF:

0.0520

GnomAD4 genome

AF:

0.0502

AC:

7635

AN:

151998

Hom.:

385

Cov.:

AF XY:

0.0517

AC XY:

3844

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.0116

Gnomad4 AMR

AF:

0.138

Gnomad4 ASJ

AF:

0.0488

Gnomad4 EAS

AF:

0.196

Gnomad4 SAS

AF:

0.0228

Gnomad4 FIN

AF:

0.0512

Gnomad4 NFE

AF:

0.0454

Gnomad4 OTH

AF:

0.0452

Alfa

AF:

0.0531

Hom.:

604

Bravo

AF:

0.0612

TwinsUK

AF:

0.0483

AC:

179

ALSPAC

AF:

0.0493

AC:

190

ESP6500AA

AF:

0.0136

AC:

ESP6500EA

AF:

0.0433

AC:

372

ExAC

AF:

0.0726

AC:

8816

Asia WGS

AF:

0.0780

AC:

270

AN:

3478

EpiCase

AF:

0.0408

EpiControl

AF:

0.0431

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 23, 2012	Arg5139Met in exon 45A of TTN: This variant is not expected to have clinical sig nificance because it has been identified in 4.5% (316/7018) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS/; dbSNP rs66677602) -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.95

Eigen

Benign

-0.0059

Eigen_PC

Benign

-0.024

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.35

MetaRNN

Benign

0.0011

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

P;P;P;P;P;P;P

PROVEAN

Benign

1.1

REVEL

Benign

0.16

Sift

Pathogenic

0.0

Sift4G

Benign

0.27

Polyphen

0.99

Vest4

0.20

ClinPred

0.022

GERP RS

5.2

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